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The cover for issue 44 of Oncotarget features Figure 1, "Schematic diagram of the human IGF2 gene structure," by Radhakrishnan, et al. recently published in "Methylation of a newly identified region of the INS-IGF2 gene determines IGF2 expression in breast cancer tumors and in breast cancer cells" which reported that these authors previously demonstrated that IGF2 protein levels are higher in BC tissues from African American women than in Caucasian women.

They also showed that high IGF2 protein levels are expressed in normal breast tissues of African American women while little or no IGF2 was detected in tissues from Caucasian women.

Thus, they designed this study to determine if differentially methylated regions of the IGF2 gene correspond to IGF2 protein expression in paired breast tissues and in BC cell lines.

The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

"The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer."

Since IGF2 promotes metastasis and chemoresistance, we propose that IGF2 levels contribute to BC aggressiveness.

Dr. Daisy D. De León from The Loma Linda University School of Medicine said, "Insulin-Like Growth factor 2 (IGF2) is a fetal growth factor that plays a critical function in fetal differentiation and metabolism by signaling through the IGF-I receptor and the insulin receptor."

Thus, IGF2 expression is important in normal breast development and increased IGF2 expression in the mammary gland contributes to BC malignancy.

This gene is located on the short arm of chromosome 11 at position 15.5. Methylation of the IGF2 gene regulatory regions occurs during the formation of an egg or sperm cell, and it is distinct and differentially modified depending on the parental origin of the allele.

In particular, dysregulation in the methylation of the IGF2 gene promoters occurs in several cancers including BC and this altered methylation leads to different clinical features in BC disease.

In spite of these advances, there is currently no consensus regarding the methylation status of the IGF2 gene, and its relationship to the levels of IGF2 protein expressed in normal breast or in breast cancer tissues.

DNA methylation patterns of the IGF2 gene were also analyzed in several BC cell lines to determine if there was a correlation between methylation of the IGF2 gene regulatory regions and the cellular expression levels of IGF2 protein.

The De León Research Team concluded in their Oncotarget Research Paper, "the present study shows that IGF2 expression in BC cells and in paired Normal- Malignant breast tissues are determined by the methylation of a novel region in the INS-IGF2 locus. We are currently studying the mechanisms underlying the methylation of the INS-IGF2 and how they control IGF2 expression. Upregulation of IGF2 in terms of the methylation patterns of the DVDMR may have an important function in the tumorigenesis of the breast. In conclusion, we propose that the INS-IGF2 DVDMR may be a useful tool to identify women at risk of developing a more aggressive BC disease."

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DOI - https://doi.org/10.18632/oncotarget.27655

Full text - https://www.oncotarget.com/article/27655/text/

Correspondence to - Daisy D. De León - ddeleon@llu.edu

Keywords -
IGF2,
INS-IGF2,
hypermethylation,
DMR,
epigenetics

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Journal

Oncotarget

DOI

10.18632/oncotarget.27655

UNIVERSITY PARK, Pa. -- A large-scale study of African elephant genetics in Tanzania reveals the history of elephant populations, how they interact, and what areas may be critical to conserve in order to preserve genetic diversity for species conservation. The study, by researchers at Penn State, appears online in the journal Ecology & Evolution and is the first to explore gene flow -- a process vital to maintain necessary genetic diversity for species survival -- between protected areas in Africa.

"Elephants are a hallmark of the savannah, but poaching and habitat loss and fragmentation have led to major population declines across Africa," said George Lohay, postdoctoral scholar in biology at Penn State and first author of the paper. "Human activities accelerate the loss of elephant habitat, as well as the land between protected areas. Maintaining connectivity between protected areas may be especially important for this far-ranging species, particularly with regard to gene flow, which can improve genetic diversity and help buffer small populations against disease and other threats."

The researchers compared both nuclear and mitochondrial DNA of 688 elephants across Tanzania from 4 major areas with large elephant populations. These include the Serengeti and Tarangire-Manyara in north-east Tanzania, Ruaha in south-central Tanzania, and Selous in southeast Tanzania. Each contains several areas with varying levels of protection, including national parks, game reserves, and private land conserved for livestock and wildlife tourism. Many of the wildlife corridors -- the areas between these protected areas -- have closed completely due to human activity.

The researchers suspected that the East African Rift Valley that runs between several protected areas would prevent gene flow between elephant populations. But, interestingly, they found that elephants from Lake Manyara National Park were in some ways more genetically similar to elephants across the rift in the Ngorongoro Conservation Area -- in the Serengeti region -- compared to elephants in the closer Tarangire National Park.

"Even though there are no physical barriers between elephants in Lake Manyara and Tarangire, there is very limited gene flow between the two populations," said Douglas Cavener, professor of biology at Penn State and an author of the paper. "It may be that cultural or behavioral barriers play a role instead. Other studies have tracked elephants moving between the two areas, but they don't appear to be mating with each other."

The similarities among the two groups across the rift suggests that there was gene flow between Ngorongoro and Lake Manyara sometime in the past.

"There is anecdotal evidence from the 1970s of elephants actually climbing across the rift, but most of the corridors connecting Ngorongoro and Lake Manyara have since become occupied by humans," said Cavener. "The Lake Manyara population is now almost completely isolated and contains only about a hundred individuals. The loss of gene flow through these corridors may lead to negative consequences due to inbreeding over the next few generations."

The researchers also found that elephants in Tarangire were genetically similar to those more than 400 km to the south in Ruaha. This suggests extensive gene flow between the two populations before the corridors were closed between them.

"Because elephants are long-lived and because mutation is a slow process, it can take multiple generations to see genetic differences between populations," said Cavener.

"We know there was significant gene flow between elephants in Tarangire and Ruaha in the recent past, but the corridors between the areas are currently blocked. Opening up these corridors could encourage gene flow, which can help maintain more genetically robust populations," added Lohay

The researchers also suspected that the Eastern Arc Mountains in southern Tanzania could prevent gene flow between populations on opposite sides of the mountains in Ruaha and Selous. But while the populations had somewhat similar nuclear DNA, their mitochondrial DNA, which is passed on primarily through the maternal line, was much more varied.

"While female elephants tend to remain in the groups where they were born, males are ejected from the herd when they reach sexual maturity, which can facilitate gene flow between groups," said Lohay. "When you see lots of differences in mitochondrial DNA markers but relatively few differences in nuclear markers, it can be a hint that males are migrating but females are not. It's a crude measurement, but that might be what are seeing here. In the future, we'd like ascertain the parentage and relationships between individuals so we can better understand the role of males in gene flow in these populations."

The study also sheds light onto the history of recolonization of the Serengeti, where elephant populations were almost completely wiped out due to poaching in the late 1800s and, after rebounding somewhat in the 1960s, drastically declined again in the 1980s. The researchers found that mitochondrial DNA of elephants in the northern Serengeti differed from those in the southern Serengeti, suggesting that two distinct groups of elephants arrived from outside the area in the early 1960s when recolonizing the area.

"Understanding these relationships and population histories can help inform future conservation efforts," said Lohay. "This study provides a baseline for future genetic studies on these remarkable animals. We also provide recommendations for wildlife corridors that should be prioritized for conservation in order to maintain potential gene flow between populations. Although we can't be certain elephants will use certain corridors, at the moment they have limited options and are facing serious habitat losses due to human encroachment."

SUMMARY

Researchers at the George Washington University have developed a new design of vertical-cavity surface-emitting laser (VCSEL) that demonstrates record-fast temporal bandwidth. This was possible by combining multiple transverse coupled cavities, which enhances optical feedback of the laser. VCSELs have emerged as a vital approach for realizing energy-efficient and high-speed optical interconnects in data centers and supercomputers.

THE SITUATION

VCSELs are a vital class of semiconductor laser diodes accompanying a monolithic laser resonator that emits light in a direction perpendicular to the chip surface. This class of lasers is gaining market importance given their compact size and high optoelectronic performance. As miniaturized lasers, they are used as an optical source in highspeed, short-wavelength communications and optical data networks. Dense traffic and high-speed transmission are key requirements for smart sensor applications in automotive or in data communications, which are enabled by compact and high-speed VCSELs. However, the 3-dB bandwidth, known as the speed limit of VCSELs, is limited by thermal effects, parasitic resistance, capacitance and nonlinear gain effects.

THE SOLUTION

Direct modulation of VCSELs cannot exceed about 30 GHz due to nonlinear optical amplification effects known as gain relaxation oscillations. This invention introduces a revolutionary novel VCSEL design. Since feedback inside the laser needs to be carefully managed, researchers introduced a multi-feedback approach by combining multiple coupled cavities. This allowed them to strengthen the feedback known as "slow-light," thus extending the temporal laser bandwidth (speed) beyond the known limit of the relaxation oscillation frequency. The innovation is ground-breaking because the direct feedback from each cavity only needs to be moderate and can be controlled precisely via the coupled cavities, allowing for a higher degree of design freedom. Following this coupled cavity scheme, a resulting modulation bandwidth in the 100 GHz range is expected.

FROM THE RESEARCHERS

"Here we introduce a paradigm-shift in laser design. We utilize a novel coupled cavities approach to carefully control the feedback to the laser achieved by significantly slowing the laser light down. This coupled cavity approach adds a new degree of freedom for laser design, with opportunities in both fundamental science and technology."
- Volker Sorger, associate professor of electrical and computer engineering at the George Washington University.

"This invention is timely since demand for data services is growing rapidly and moving towards next generation communication networks such as 6G, but also in automotive as proximity sensor or smart phone's face ID. Furthermore, the coupled cavity system paves a way for emerging applications in quantum information processors such as coherent Ising machines."

New Rochelle, NY, November 19, 2020--Black, Hispanic, and Native American students and faculty are largely underrepresented in environmental engineering programs in the United States. A pathway for increasing diversity and community participation in the environmental engineering discipline is proposed in the peer-reviewed journal Environmental Engineering Science. Click here to read the article now.

"As a community, environmental engineering professors must examine all aspects of academic institutions to combat systemic racism, including teaching, research and university administration. This article presents a strategic plan for expanding the horizons of students and fostering faculty careers in a way that advances our mission," says Catherine A. Peters, PhD, Editor-in-Chief of Environmental Engineering Science and Professor, Department of Civil & Environmental Engineering, Princeton University.

Lupita Montoya, University of Colorado Boulder, and coauthors propose exposing students to community-based participatory methods, establishing action research groups for faculty, and broadening the definition of research impact to improve tenure promotion experiences for minority faculty.

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2019.1261, Yue Wu, Guoyue Zhang, Rong Hu and Jianlin Du from The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China consider the risk of target organ damage in patients with masked hypertension versus sustained hypertension.

The authors compared the risk of target organ damage in masked hypertension (MH) and sustained hypertension (SH) through a systematic review and meta-analysis of PubMed, Embase, and the Cochrane Library of relevant case-control studies. Articles on MH and SH were selected according to the inclusion criteria and were analyzed. The primary end point was target organ damage in the heart. The secondary end points were target organ damage in the kidneys and blood vessels.

Seventeen studies that met the screening criteria were included in the meta-analysis. Compared with the SH group, in the MH group carotid intima-media thickness (IMT) and E/A ratio were significantly greater and the prevalence of left ventricular remodeling and the pulse wave velocity were significantly lower. Other indicators in the heart, kidneys, and blood vessels were not statistically different between the two groups. IMT: P=0.01, E/A ratio: P=0.01, prevalence of left ventricular remodeling: P=0.02, pulse wave velocity: P=0.01.

The study shows that MH may have almost the same degree of target organ damage as SH, so clinicians may need to consider target organ damage.

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2019.0585, Lei Zhang, Tiewei Lv, Xiaoyan Liu, Chuan Feng, Min Zheng, Jie Tian and Huichao Sun from the Children's Hospital of Chongqing Medical University, Chongqing, China and the Chongqing Key Laboratory of Pediatrics, Chongqing, China consider a case of pediatric heart failure caused by anomalous origin of the left coronary artery from the pulmonary artery.

A female patient aged 3 months and 10 days was admitted to the cardiology department due to symptoms of heart failure. According to the echocardiography results, the patient received a diagnosis of primary endocardial fibroelastosis and was treated with γ-globulin, prednisone, digoxin, and diuretics. Coronary computed tomographic angiography and coronary angiography were performed as there was no improvement after 2 months of treatment. Finally, the patient received a diagnosis of anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA).

ALCAPA is a rare congenital heart defect that can cause severe heart failure during infancy, and is easily misdiagnosed clinically. In this report, the authors demonstrate the process of misdiagnosis of the case and review the relevant literature, to improve the understanding and early diagnosis of ALCAPA.

For a slow-growing microbe that multiplies infrequently, Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB) has long puzzled researchers as to how it develops resistance to antibiotics so quickly, in a matter of weeks to months.

Now, TB researchers at San Diego State University have uncovered a crucial clue to the mystery: the answer may lie in the epigenetic domain rather than the genetic domain where most scientists have concentrated their efforts.

Their discovery could help advance new diagnostics, therapeutics and vaccine targets.

Epigenetics is the study of inheritable changes in gene expression that do not involve a corresponding change to the underlying DNA sequence -- meaning changes to the phenotype but no change in the genotype. This affects only the physical structure of the DNA, through a process called DNA methylation where a chemical 'cap' is added to the DNA molecule, preventing or facilitating the expression of certain genes.

The SDSU researchers describe the rapid response phenomenon they discovered as 'intercellular mosaic methylation,' a process by which Mycobacterium tuberculosis diversifies, creating multiple subpopulations each with its own phenotype. While antibiotics could kill many of these mutant subpopulations, at least a few do survive and develop drug resistance.

"We believe this also explains why diagnostic testing in some patients does not predict treatment failure, and why some patients come back months later with the disease reemerging in a far more resistant state," said Faramarz Valafar, a TB expert with SDSU's School of Public Health who studies the genetics and epigenetics of pulmonary diseases. "This is also why CT scans of the lungs of many "cured" patients show lesions with possible bacterial activity."

Worldwide, TB is among the top 10 causes of death. It killed 1.4 million people in 2019, and about 10 million people fall ill with it each year, according to the World Health Organization.

Valafar's team collected hundreds of samples of drug resistant varieties of the bacteria from patients in India, China, Philippines and South Africa, as well as Europe, through collaborations with TB researchers worldwide.

Their study was published in eLife in late October. Valafar and project scientist Samuel Modlin began exploring epigenetics for the TB bacterium in 2016, and doctoral student Derek Conkle-Gutierrez joined them in 2018, in the Laboratory for Pathogenesis of Clinical Drug Resistance and Persistence. Modlin, an SDSU alumnus, and Conkle-Gutierrez utilized skills and knowledge they acquired at SDSU to carry out this research -- data and statistical analysis, coding skills, and bioinformatics knowledge.

"We've known for decades that bacterial epigenetics can influence the expression of certain genes, which can lead to a variety of phenotypes even when they have identical genotypes," Conkle-Gutierrez said. "We discovered evidence of that phenomenon in the TB bacterium."

Antibiotic resistance is typically caused by genomic mutations, but this bacterium is one of several that leverages alternative mechanisms in the epigenetic domain to enable rapid adaptation.

"We found that some of them had mutations that led to variable DNA methylation and those strains had much more diversity in their epigenome, and thus more potential to be drug resistant," Modlin said.

The researchers found there were no set patterns and methylation was fairly random. They used advanced comparative genomic and epigenetic techniques to identify variations across cells within a colony from a single isolate, from a single patient -- including tiny variations that nevertheless impacted gene expression. They were able to do this because, rather than assuming the reference genome has a common structure, they reconstructed each genome from scratch and analyzed its epigenetic signatures.

They will now focus on testing and confirming the key genes they identified with methylation signatures. There is more work to be done before their discovery can eventually be used for diagnostics.

"There is a lot of resistance in TB that escapes current molecular diagnostics and we don't really know why. That's problematic," Valafar said. "This study offers a new domain, new tools, and a new approach to looking for alternative mechanisms. We move away from the classical view of molecular diagnostics and use a novel, comprehensive approach to analyzing bacteria."

Current standard of care treatments use two types of antibiotics -- bacteriostatics that prevent bacteria from multiplying but don't kill them, and bactericides that do kill them.

"We found a new mode of variation and if we can inhibit that diversification mechanism, we can inhibit short-term epigenetic resistance and kill the bacteria before mutations in the genome develop and cause long-term, genetic resistance," Modlin said.

This may be how some bacterial populations survive treatment and make the patient ill again with far greater antibiotic resistance or hypervirulence.

Millirobots that can adapt to unstructured environments, operate in confined spaces, and interact with a diverse range of objects would be desirable for exploration and biomedical applications. However, the development of millirobots has faced difficulty due to their complicated fabrication techniques.

Recently, researchers from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, together with the City University of Hong Kong (CityU), have developed an agglutinate, reprogrammable, disintegrable and biocompatible magnetic spray (M-spray) that can easily turn inanimate objects into millirobots.

The research findings have been published in Science Robotics in an article entitled "An agglutinate magnetic spray transforms inanimate objects into millirobots for biomedical applications."

The magnetic spray (M-spray) is mainly composited from polyvinyl alcohol (PVA), gluten and magnetic particles. The M-skin formed from the M-spray is reprogrammable by adjusting the easy magnetization direction without changing the main structure.

When the covered spray is thoroughly wetted, the spacing between magnetic particles increases due to PVA swelling, and the constraints on magnetic particles from the PVA and gluten are greatly decreased. As a result, the magnetic particles inside the spray can be realigned along the direction of magnetic flux and can overcome constraints when a strong magnetic field is applied.

"The on-demand reprogramming ability endows millirobots with high adaptivity to achieve diverse locomotion. The team demonstrated the reprogramming of a three-section reptile millirobot that could move with 3D caterpillar motion before reprogramming and 2D concertina after reprogramming," said co-first author Dr. SHANG Wanfeng, associate professor at SIAT.

Moreover, the M-spray can be disintegrated by increasing the kinetic energy of magnetic particles to overcome inner constraints. This is done by applying an oscillating magnetic field in an aqueous environment. This magnetically induced disintegration ensures the constructed millirobot can disintegrate on command.

The research also proved potential applications in the biomedical area, including the navigation ability of an M-spray-covered catheter in the narrow vascular model, the reprogramming of multipoint sampling cotton thread for various sets of steering, and a magnetic spray-covered capsule for active delivery.

A rabbit stomach experiment demonstrated that a constructed capsule millirobot could effectively enhance the retention as well as the concentration of a drug in specific lesions.

"This research offers a general on-demand robot construction method by leveraging the structure and morphology of the targeted objects themselves. With biocompatible components, the side effects from its disintegration are negligible, making it a good candidate for biomedical applications," said Dr. WU from SIAT.

Lithium-ion (Li-ion) batteries are widely used in portable electronic devices, electric vehicles, and grid-scale energy storage systems. Safety of Li-ion batteries, however, has been called into question repeatedly over the past several years due to a conventional organic electrolyte causing fire and explosion in many cases. Ceramic solid-state electrolyte (SSE) thin films promise a viable solution to addressing the safety issue by blocking the lithium dendrite that causes short circuit and thermal runaway, meanwhile offering high energy density for next-generation Li-ion batteries. However, current SSE thin films have low ionic conductivities, ranging from 10?8 to 10?5 S/cm, which can be attributed to poor material quality.

A research team led by Liangbing Hu at the University of Maryland's A. James Clark School of Engineering recently developed a new method of printing and sintering a variety of SSE thin films. This work, entitled, "Printable, high-performance solid-state electrolyte films," was published on November 18, 2020, in Science Advances. The team named this method "printing and radiative heating" (PRH), which features a solution-based printable technique followed by rapid sintering.

In a typical process, a precursor suspension is printed on a substrate, whose concentration and thickness can be adjusted. The high-quality and high-performance SSE thin film can then be obtained after rapid (~3 s) high-temperature (~1500°C) sintering, ensuring minimal Li loss and high crystallinity. This approach not only leads to dense and uniform microstructure for the SSE thin films, but also ensures superior ionic conductivity. Notably, the fabrication process - from precursor to final product - only takes ~5 min, which is ~100 times faster than conventional methods.

In a proof-of-concept demonstration, the team showed a printed garnet-based SSE thin film to have high ionic conductivity of up to 1 mS/cm and excellent cycling stability. In addition, the PRH method enables many other designs such as complex multilayer assembly without cross-contamination during synthesis. It can also be extended to preparing other ceramic thin films, which opens up new opportunities in developing safe and high-performance solid-state batteries and other thin-film-based devices.

Researchers have developed a chip that is powered wirelessly and can be surgically implanted to read neural signals and stimulate the brain with both light and electrical current. The technology has been demonstrated successfully in rats and is designed for use as a research tool.

"Our goal was to create a research tool that can be used to help us better understand the behavior of different regions of the brain, particularly in response to various forms of neural stimulation," says Yaoyao Jia, corresponding author of a paper on the work and an assistant professor of electrical and computer engineering at North Carolina State University. "This tool will help us answer fundamental questions that could then pave the way for advances in addressing neurological disorders such as Alzheimer's or Parkinson's disease."

The new technology has two features that set it apart from the previous state of the art.

First, it is fully wireless. Researchers can power the 5×3 mm2 chip, which has an integrated power receiver coil, by applying an electromagnetic field. For example, in testing the researchers did with lab rats, the electromagnetic field surrounded each rat's cage - so the device was fully powered regardless of what the rat was doing. The chip is also capable of sending and receiving information wirelessly.

The second feature is that the chip is trimodal, meaning that it can perform three tasks.

Current state-of-the-art neural interface chips of this kind can do two things: they can read neural signals in targeted regions of the brain by detecting electrical changes in those regions; and they can stimulate the brain by introducing a small electrical current into the brain tissue.

The new chip can do both of those things, but it can also shine light onto the brain tissue - a function called optical stimulation. But for optical stimulation to work, you have to first genetically modify targeted neurons to make them respond to specific wavelengths of light.

"When you use electrical stimulation, you have little control over where the electrical current goes," Jia says. "But with optical stimulation, you can be far more precise, because you have only modified those neurons that you want to target in order to make them sensitive to light. This is an active field of research in neuroscience, but the field has lacked the electronic tools it needs to move forward. That's where this work comes in."

In other words, by helping researchers (literally) shine a light on neural tissue, the new chip will help them (figuratively) shine a light on how the brain works.

A team of dentists from RUDN University confirmed that a change in the dominant side of chewing is a reason for the early deterioration of dental implants. Such a change makes it more difficult for a patient to get accustomed to an implant and can lead to bone tissue abnormalities. The discovery can help dentists plan the recovery process after implantation surgeries. The results of the study were published in the European Journal of Dentistry.

Every year, around 2 mln dental implants with fixed dentures attached to them are installed all over the world. An implant is an effective way to restore a deformed or lost tooth without negatively affecting a patient's quality of life. Modern-day dental implants, usually made of titanium, are durable and quick to take in the bone tissue of a jaw. The only issue with them is their early deterioration in 4-5% of patients. Such deterioration is caused by microdamage that occurs when the load on the implant is calculated incorrectly before the surgery. Excessive load affects the junction between the metal and the bone, letting the bacteria in under the implant and causing inflammation. A team of dentists from RUDN University suggested that additional load on the implant might occur when a patient changes the dominant side of chewing in the first months after the surgery.

Most people don't chew symmetrically on both sides of the jaw but have a dominant side that accounts for up to 75% of chewing movements. However, such a side can be changed, for example, because of a sore tooth. It usually takes a patient 3 to 4 months to get accustomed to a dental implant and during this time the type of chewing and the load on the teeth can change. As a result, after the surgery, a patient can switch to a different side of chewing, and load calculations from before the surgery can become invalid. Until recently, the effect of this dramatic change in chewing habits on the state of dential implants remained understudied.

The team monitored the course of rehabilitation of 64 patients with dental implants. The participants of the study were adults with implants installed only on one side of the jaw. Surgeries on both sides of the jaw were not included in the study as they would not allow for measuring the effect of dominant chewing side change. The team took X-ray images of the participants' teeth, measured the strength of their chewing muscles, and in some cases took CT images of the jaws. All these operations were conducted once before the surgery and twice within a year after it. To analyze the results of the treatment, the team asked the participants to fill in questionnaires.

40 patients (62.5%) reported changes in the dominant side of chewing after the surgery. According to the dentists, this might have happened because the patients returned to the chewing patterns they had been used to earlier, before losing a tooth. Having compared this group with the rest of the patients that reported no changes in their chewing habits, the team found out that a change of the dominant side of chewing leads to more bone tissue formation pathologies. In 4 patients with changed chewing habits, the first signs of issue deterioration around the implant were visible in X-ray images. As for the second group, these signs were identified in only one participant. Six months after the surgery the patients that changed their dominant side of chewing felt 22% less adapted to the implants than the patients with no changes in their chewing patterns.

"A change in the dominant side of chewing is an important factor in one's adaptation to dental implants. According to our study, it can also be the reason for pathological processes, eventually leading to the loss of an implant. Dentists need to be aware of the prevalence of such changes, consider them when developing postsurgical rehabilitation plants, and look for their signs during regular checkups," said Prof. Igor Voronov, MD, from the Department of Orthopedic Dentistry, RUDN University.

Researchers at Baylor College of Medicine, the Broad Institute of MIT and Harvard and other institutions have applied powerful proteogenomics approaches to better understand the biological complexity of breast cancer. With this approach, the researchers were able to propose more precise diagnostics for known treatment targets, identify new tumor susceptibilities for translation into treatments for aggressive tumors and implicate new mechanisms involved in breast cancer treatment resistance. The study appears in the journal Cell.

Proteogenomics combines laboratory techniques for next-generation DNA and RNA sequencing with mass spectrometry-based analysis for deep, unbiased quantification of proteins and protein modifications in cancer cells, along with computational methods for integrated analysis of this data. Such proteogenomic approaches have been extensively applied to study cancers by investigators at the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (NCI-CPTAC).

"Importantly, our analysis included identification of phosphorylation and acetylation, protein modifications that reveal information about the activity of individual proteins. Protein acetylation had not been profiled in breast cancer before. These new approaches promise biological insights into difficult to treat breast cancers and the ability to dissect response heterogeneity," said co-corresponding author Dr. Matthew Ellis, breast cancer oncologist and professor and director of Baylor College of Medicine's Lester and Sue Smith Breast Center, McNair Scholar at Baylor and Susan G. Komen Scholar.

Simultaneously analyzing changes in the genetic code and the resulting alterations in terms of protein function provides a much more complete picture of what is going on inside breast cancer tumors than analyzing each component in isolation.

More precise data

The researchers' initial proteogenomic analysis of breast cancer using residual samples from the Cancer Genome Atlas provided proof-of-principle that proteogenomics represented an advance in breast cancer profiling. The current study represents a major step forward in that it included tissue samples that were collected using protocols that specifically preserve protein modifications, analyzed many more samples, carried out genomics and proteomic characterization on exactly the same tissue fragments, and added protein acetylation profiling to protein phosphorylation, DNA and RNA measurements. Proteogenomic analytical techniques have matured substantially in recent years, and those cutting-edge approaches were applied to this dataset.

The researchers completed proteogenomic analyses of 122 treatment-naïve primary breast cancer samples. Their measurements generated a tremendous amount of data ? about 38,000 protein phosphorylation sites and almost 10,000 protein acetylation sites per tumor, as well as whole exome and RNA sequencing ? necessitating advanced computational methods for analyzing and integrating the information. "Complex analyses like these are now routinely being performed on large-scale proteogenomic data sets, and we are developing tools to automate the process," said Dr. D.R. Mani, a co-corresponding author and principal computational scientist at Broad.

"We describe here proteogenomic characterization of the largest set to date of breast cancer samples that were purposefully collected for these types of analyses, maximizing the fidelity and accuracy of the results," Ellis said. "Each tumor cell has literally hundreds of genomic changes. Mostly we don't understand their significance either clinically or biologically. The approach we illustrate enables a deeper and more complete understanding of each individual's breast cancer."

Identifying drug targets

For example, the analyses revealed that some subtypes of breast cancer have certain targetable enzymes called kinases that are more heavily phosphorylated than in other cancers, suggesting greater activity and therefore targetability. These analyses included recently identified drug targets such as CDK4/6 and its regulatory context, as well as programmed cell death receptors and ligands that are the targets of new immunotherapy drugs. The integrated analyses also identified new sets of estrogen receptor-positive breast cancers that could be treated with these agents. This is significant because currently these agents are restricted to estrogen receptor-negative disease.

Additional analyses raised entirely new insights into the metabolic vulnerabilities of ER+ and ER- breast cancer. "Our global analysis of the acetylproteome, the first in breast tumors, exposed new details of breast cancer subtype-specific metabolism," said co-corresponding author Dr. Steven A. Carr, director of proteomics at Broad.

Improving diagnosis and treatment

The researchers hope that their findings will motivate breast cancer scientists to explore the therapeutic or diagnostic potential of the new biological alterations they have identified in this study. They also are optimistic that their findings will encourage an effort to translate proteogenomics into a cancer-profiling approach that can be used routinely in the clinic to improve diagnosis and treatment.

"We believe that proteogenomics approaches will continue to help us to identify new candidate therapeutic targets, better understand the immune landscape of breast and other cancers, gain insights into response and resistance, and ultimate progress toward our goal of personalized cancer care," noted co-corresponding author Dr. Michael Gillette, a pulmonary and critical care physician at Massachusetts General Hospital and senior group leader in proteomics at Broad. "The science is powerful and exciting, but in the end it is what we can deliver to the patient that makes it important."

Find the complete list of all the contributors to this work and their affiliations, as well as all the financial support for this study in the journal Cell.

In the United States alone, over 14 million adults suffer from alcohol use disorder. For those that seek treatment, 90% will experience at least one relapse within the first four years. One reason for this is that alcohol withdrawal directly impacts the brain's stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol?seeking behaviors.

Dr. Steve Ramirez, Assistant Professor of Psychological & Brain Sciences at Boston University and research director at 1907 Research, is the principal investigator of The Ramirez Group, where he leads research on how memory works and how to hijack it to treat disorders of the brain.

Ramirez, together with researcher Christine Cincotta, recently examined whether the effects of alcohol addiction in the brain could be modified through memory manipulation. To do this, the researchers studied alcohol exposure and withdrawal in mice to see if they were able to affect their responses to traumatic experiences. Using optogenetics, a technique that uses light and genetic engineering to control the cells of the brain, the researchers were able to artificially dampen fear responses in mice and mitigate addiction-related behaviors. Their findings were published in Hippocampus.

How exactly did the researchers pull this off and what are the future implications? Read below for a Q&A with Ramirez and Cincotta to learn about the motivation behind their work, the findings, and what they hope to study next.

1) What happens to a person's brain when they are addicted to alcohol and go through withdrawal?

Cincotta: When an individual consumes alcohol, the alcohol enters your bloodstream and crosses into your brain where there's a cascade of effects across many regions. Alcohol is considered a depressant, meaning it slows down your brain, and various regions and pathways can change and adapt (structurally and functionally) following chronic, heavy drinking. After a person develops a dependency, going through withdrawal results in a negative affective state, where the individual can experience increased stress and anxiety, likely leading the individual to crave and seek alcohol.

Ramirez: Withdrawal from alcohol tends to increase negative emotions which can compromise the ability to properly process aversive events. In other words, these aversive events can be perceived to be even more negative than usual as a result of withdrawal.

2) What did you aim to study with your research? What made you want to examine this issue?

Cincotta: Alcohol is known to have effects on the brain's stress and memory systems. Something I'm really interested in is the intersection of memory and addiction research. Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are often researched in isolation, however in the real world the comorbidity of these two disorders is a huge public health concern. Depending on which populations are taken into account, the comorbidity of AUD and PTSD can range from 30-60%. For this study, we were interested in looking at the effects of alcohol exposure and withdrawal on how mice were able to process and attenuate their responses to a traumatic experience. Moreover, we were also looking to mitigate these effects artificially. The use of animal models, in particular rodents, allow researchers like myself to better understand and dissect not only how the brain functions, but also how it malfunctions.

Exposure therapy is a common clinical approach used to treat stress, memory, and addiction related disorders, where patients are continually exposed to a specific anxiety trigger in a safe, controlled environment. In research we call this extinction training. The intention is that continuous exposure will help to overcome stress-related anxieties, and over time the animal will update their fear memories and learn that the context is safe again. However, in rodent models of alcohol use disorder, studies have shown significant impairments in the ability of an alcohol-withdrawn rodent to attenuate fear memories and behaviors by extinction learning. The neural circuits that underlie this impairment in rodents likely exist in individuals who struggle with PTSD and AUD.

To give mice PTSD, we utilize contextual fear conditioning. To do this, we place a mouse in a small chamber they've never seen before. Mice are naturally inquisitive and will explore novel environments if there is no threat. After giving them a few minutes to explore, the mice receive four mild footshocks about a minute apart. Mice, when scared, will exhibit an innate fear-response behavior known as "freezing." Mice tend to stay in the corner of the box, hunched over, and completely still. Extinction training consists of continually placing the mouse back into this same box, and over time the mouse will freeze less and less as they update their memory and re-learn that the chamber is no longer a threatening place.

3) Walk us through your experiments? What did the findings reveal?

Ramirez: Our animals first were administered chronicle ethanol to generate an addiction-related state and they began showing abnormally heightened fear responses. Next, we found the cells processing a fear memory in particular and genetically engineered those cells to become light-sensitive so that we could optically activate them using optogenetics. Then, we activated these cells repeatedly in an attempt to artificially dampen the fear responses, which surprisingly worked! We were thrilled that we could optogenetically mitigate these addiction-related behaviors in general.

4) What was the most surprising finding?

Cincotta: The "replication crisis" is a well known issue within academia, especially in psychology and behavioral neuroscience. The first experiment was all about replicating findings in our lab, however the extinction paradigm we used was different from previous studies. In the literature, I was only able to find extinction paradigms that involved putting the mice in the context once per day, whereas we placed our mice in the chamber two times every day. In both experiments, we noticed a "zig-zag" effect with freezing levels, where mice froze higher in the morning session than in the afternoon. This was most prominent with the alcohol-exposed mice in Experiment 1, as they froze significantly higher than saline control animals in the morning sessions, but not in the afternoon session. We were curious about possible effects of time of day, reconsolidation (or the "updating" of a memory that can occur once a memory itself is recalled), and found it really surprising that the alcohol exposed mice didn't necessarily have an extinction-learning impairment, but rather an extinction-recall impairment.

5) What is the significance of these findings?

Cincotta: Optogenetic technology as it stands today is too invasive to be used in humans, however there are some other groups working on developing non-invasive optogenetic tools. Nonetheless, discoveries made will continue to expand society's knowledge of neural circuits and in turn, inform future treatments and change how we treat patients with disorders such as PTSD and AUD.

6) What do you hope to study next?

Cincotta: I've recently started a new project based on some of the findings from this study. Another known behavioral effect in mice withdrawn from alcohol is maladaptive "generalization." Mice that are fear conditioned in one context should not exhibit fear responses in a novel, safe context. However, mice that have been exposed to and withdrawn from alcohol will generalize their fear memories across novel contexts.

In my new project, I'm looking to better understand the hippocampal dynamics of fear generalization, first by tagging and inhibiting the fear engrams in different contexts, and also by implanting mice with miniature microscopes so that I can view and analyze the cells in awake, behaving, freely moving mice as the mice are exposed to different contexts.

Congenital adrenal hyperplasia (CAH) is a disorder that affects the adrenal gland's ability to release hormones that regulate the body's response to stress and illness. CAH is treatable, but can be potentially life-threatening during illness or if not managed. The disorder is difficult to identify, and much still needs to be understood about the condition. But new research conducted at Children's Hospital Los Angeles has shown that computers may be able to use subtle facial features to recognize CAH. This finding could lead to better identification of the disorder and better care of CAH patients.

"In endocrinology, CAH is one of the few emergency conditions we encounter," says Mimi Kim, MD, MSc, co-Director of the CAH Comprehensive Care Clinic at Children's Hospital Los Angeles. "It's the leading cause of adrenal insufficiency in children, which means the body can't produce aldosterone, adrenaline and cortisol."

These hormones allow the body to manage blood pressure and respond to crises. In addition, CAH is marked by higher levels of the sex hormone testosterone. This can lead to changes in genitalia for female patients. But testosterone has another effect not directly linked to sex or gender--an effect that could be used to help identify CAH.

"It's pretty well accepted that hormones like testosterone help to shape facial features," says Dr. Kim. "Since CAH causes high testosterone during development, it stands to reason that differences, even subtle ones, could be present in CAH patients." This, she says, led her to wonder whether facial morphology--a collection of physical traits--could assist clinicians in identifying patients with CAH.

"There was no established link yet between CAH and facial morphology," says Dr. Kim. This could be because facial differences are subtle enough to be missed by most clinicians. "But advances in machine learning have come a long way," she says, "especially in facial recognition."

Dr. Kim teamed up with engineers and scientists from the University of Southern California Information Sciences Institute to design and test her hypothesis. The team loaded images of 102 patients with CAH and 144 control individuals into computers that were trained in facial recognition. Through machine learning, the computers were able to identify subtle differences in facial morphology and correctly identify the patients with CAH with greater than 90% accuracy.

The study represents an important step in the path to better identifying and understanding CAH. The findings establish, for the first time, that not only is there a link between facial morphology and CAH, but computers can detect this link and predict CAH based on facial features of patients.

Although newborns are routinely screened for CAH, genetic tests are expensive and difficult to obtain, and it's not simple to characterize severity of the condition. "We really need a more sensitive, easier way," says Dr. Kim. "It's my hope that this is it; that we can use the best that technology has to offer to better understand CAH and help our patients."

It hasn't been more than a year and a half since the international researchers' network SPI-Birds started officially. Together they collect, secure and use long-term breeding population data of 1.5 million individually recognisable birds... and counting. Big questions in ecology and evolution can be answered using this data. Today, the publication of SPI-Birds' first scientific paper in the Journal of Animal Ecology coincides with receiving the Dutch Data Incentive Prize for the Medical and Life Sciences.

"This is truly a community effort," stress both Antica Culina and Marcel Visser of the Netherlands Institute of Ecology (NIOO-KNAW). Together they form the executive board of SPI-Birds, or Studies of Populations of Individuals - Birds, a fresh but already prize-winning international research network plus database (http://www.spibirds.org). "Behind the paper describing our initiative, there are around 120 people and 1.5 million individually marked birds from 80 populations and 19 species. And an army of people who have been collecting these data, in sunshine and rain, adding up to over 2000 seasons of fieldwork." These studies are at the core of what we know about evolutionary and ecological processes in the wild.

Researchers Culina and Visser feel honoured that SPI-Birds has received this Dutch Data prize. "The prize not only recognises the importance of the SPI initiative, but also that FAIR (Findable, Accessible, Interoperable and Reusable) data, and not necessarily Open Data, might be the most viable approach for many research communities at the moment."

Tale with a long tail

The SPI-Birds story started about three years ago. Why should combining bird data from various populations across Europe be such a hassle, wondered Culina. As a young science mum to be, the last thing she needed was something else to keep her up at night. And she was not the only one who was thinking this way. Her collaborator and two-times professor, Marcel Visser, had already worked with such long-term data sets of great tits, blue tits and other hole-breeding birds for three decennia. And he, like many others, was very well aware of the wider-felt need for a unifying database and data standard. So actually, the story is quite a bit older.

The goals were clear: preventing data loss, making it much easier for people to use the data, and increasing future data quality with a community-supported standard. And so, they finally made that happen. Visser: "SPI-Birds is important, because it allows comparative studies among populations by making the data FAIR. Converting the various data formats into a single standard data format, especially, really facilitates the use of the data."

Inspire communities

The first SPI Bird paper aims not to present scientific results, but to describe the network for new members and stakeholders, and its 'lessons learned' in order to inspire other communities. "We hope SPI-Birds will serve as an encouragement to other research communities to create their own standards," adds Culina. Other papers are in the pipeline, analysing the data to address scientific questions.

What more can we look forward to, coming out of this initiative? Visser: "Apart from the many scientific publications that will make use of SPI Birds, we also really hope that it will help to build a closer community, including standardisation of the collection of the data and the way data are used, which is very rare for phenotypic data." Culina elaborates: "The grand vision is a data landscape that connects different types of data, and helps us gain a thorough understanding of evolutionary and ecological patterns and processes in the wild."

Future tails

It's not the first time the SPI-Birds database and networking community has been recognised for its merits, and it probably won't be the last time either. The project is funded by NWO (Netherlands Organization for Scientific Research), the Centre for Biodiversity Dynamics (NTNU in Trondheim, Norway) and NIOO-KNAW. "We would also like to acknowledge the enormous efforts of all current and past fieldworkers that have contributed to the data collection."

"And who knows, in the future we might even see a SPI-Mammals or SPI-Lizards?"