Culture

A physicist at The University of Texas at Arlington has proposed a new concept for treating cancer cells, further advancing the University's status as a leader in health and the human condition.

In a recently published paper in the journal Nanomedicine: Nanotechnology, Biology and Medicine, UTA physics Professor Wei Chen and a team of international collaborators advanced the idea of using titanium dioxide (TiO2) nanoparticles stimulated by microwaves to trigger the death of cancer cells without damaging the normal cells around them.

The method is called microwave-induced radical therapy, which the team refers to as microdynamic therapy, or MDT.

The use of TiO2 nanoparticles activated by light and ultrasound in cancer treatments has been studied extensively, but this marks the first time researchers have shown that the nanoparticles can be effectively activated by microwaves for cancer cell destruction--potentially opening new doors to treatment for patients fighting the disease.

Chen said the new therapy centers on reactive oxygen species, or ROS, which are a natural byproduct of the body's metabolism of oxygen. ROS help kill toxins in the body, but can also be damaging to cells if they reach a critical level.

TiO2 enters cells and produces ROS, which are able to damage plasma membranes, mitochondria and DNA, causing cell death.

"Cancer cells are characterized by a higher steady-state saturation of ROS than normal, healthy cells," Chen said. "This new therapy allows us to exploit that by raising the saturation of ROS in cancer cells to a critical level that triggers cell death without pushing the normal cells to that same threshold."

The pilot study for this new treatment concept builds upon Chen's expertise in the use of nanoparticles to combat cancer.

Chen's collaborators hail from the Guangdong Academy of Medical Sciences and Beihang University. The team conducted experiments that demonstrate the nanoparticles can significantly suppress the growth of osteosarcomas under microwave irradiation.

While TiO2 and low-power microwave irradiation alone did not effectively kill cancer cells, the combination of the two proved successful in creating a toxic effect for the tumor cells. Microwave ablation therapy has already proven to be an effective treatment against bone cancer, obtaining better results than MDT. However, MDT has applications for combatting other types of cancer, not just the osteosarcomas used for this pilot case.

Using light to activate ROS--as is seen in photodynamic therapy--can be challenging for the treatment of tumors deeply located within the body; in contrast, microwaves lend the ability to create deeper penetration that propagates through all types of tissues and non-metallic materials.

"This new discovery is exciting because it potentially creates new avenues for treating cancer patients without causing debilitating side effects," Chen said. "This targeted, localized method allows us to keep healthy cells intact so patients are better equipped to battle the disease."

The results of the pilot study indicate MDT is a promising approach for cancer treatment even though the method is still being developed and its limitations explored. The research team has filed a patent for MDT. Next, they plan to turn their attention to understanding the physics and internal mechanisms behind the powerful combination of microwaves and TiO2.

"Dr. Chen continues to build a research portfolio that holds transformative implications for cancer treatment," said Alex Weiss, chair of UTA's Department of Physics. "This new work is exemplary of the spirit of discovery we strive to embody at UTA. I look forward to what Dr. Chen and his collaborators can accomplish in the coming phases of this research as they pioneer a potential new avenue for combatting cancer."

ANN ARBOR--It's one of the greatest and longest-running mysteries surrounding, quite literally, our sun--why is its outer atmosphere hotter than its fiery surface?

University of Michigan researchers believe they have the answer, and hope to prove it with help from NASA's Parker Solar Probe.

In roughly two years, the probe will be the first man-made craft to enter the zone surrounding the sun where heating looks fundamentally different that what has previously been seen in space. This will allow them to test their theory that the heating is due to small magnetic waves traveling back and forth within the zone.

Solving the riddle would allow scientists to better understand and predict solar weather, which can pose serious threats to Earth's power grid. And step one is determining where the heating of the sun's outer atmosphere begins and ends--a puzzle with no shortage of theories.

"Whatever the physics is behind this superheating, it's a puzzle that has been staring us in the eye for 500 years," said Justin Kasper, a U-M professor of climate and space sciences and a principal investigator for the Parker mission. "In just two more years, Parker Solar Probe will finally reveal the answer."

The U-M theory, and how the team will use Parker to test it, is laid out in a paper published June 4 in The Astrophysical Journal Letters.

In this "zone of preferential heating" above the sun's surface, temperatures rise overall. More bizarre still, individual elements are heated to different temperatures, or preferentially. Some heavier ions are superheated until they're 10 times hotter than the hydrogen that is everywhere in this area--hotter than the core of the sun.

Such high temperatures cause the solar atmosphere to swell to many times the diameter of the sun and they're the reason we see the extended corona during solar eclipses. In that sense, Kasper says, the coronal heating mystery has been visible to astronomers for more than a half millenium, even if the high temperatures were only appreciated within the last century.

This same zone features hydromagnetic "Alfvén waves" moving back and forth between its outermost edge and the sun's surface. At the outermost edge, called the Alfvén point, the solar wind moves faster than the Alfvén speed, and the waves can no longer travel back to the sun.

"When you're below the Alfvén point, you're in this soup of waves," Kasper said. "Charged particles are deflected and accelerated by waves coming from all directions."

In trying to estimate how far from the sun's surface this preferential heating stops, U-M's team examined decades of observations of the solar wind by NASA's Wind spacecraft.

They looked at how much of helium's increased temperature close to the sun was washed out by collisions between ions in the solar wind as they traveled out to Earth. Watching the helium temperature decay allowed them to measure the distance to the outer edge of the zone.

"We take all of the data and treat it as a stopwatch to figure out how much time had elapsed since the wind was superheated," Kasper said. "Since I know how fast that wind is moving, I can convert the information to a distance."

Those calculations put the outer edge of the superheating zone roughly 10 to 50 solar radii from the surface. It was impossible to be more definitive since some values could only be guessed at.

Initially, Kasper didn't think to compare his estimate of the zone's location with the Alfvén point, but he wanted to know if there was a physically meaningful location in space that produced the outer boundary.

After reading that the Alfvén point and other surfaces have been observed to expand and contract with solar activity, Kasper and co-author Kristopher Klein, a former U-M postdoc and new faculty at University of Arizona, reworked their analysis looking at year-to-year changes rather than considering the entire Wind Mission.

"To my shock, the outer boundary of the zone of preferential heating and the Alfvén point moved in lockstep in a totally predictable fashion despite being completely independent calculations," Kasper said. "You overplot them, and they're doing the exact same thing over time."

So does the Alfvén point mark the outer edge of the heating zone? And what exactly is changing under the Alfvén point that superheats heavy ions? We should know in the next couple of years. The Parker Solar Probe lifted off in August 2018 and had its first rendezvous with the sun in November 2018--already getting closer to the sun than any other human-made object.

In the coming years, Parker will get even closer with each pass until the probe falls below the Alfvén point. In their paper, Kasper and Klein predict it should enter the zone of preferential heating in 2021 as the boundary expands with increasing solar activity. Then NASA will have information direct from the source to answer all manner of long-standing questions.

"With Parker Solar Probe we will be able to definitively determine through local measurements what processes lead to the acceleration of the solar wind and the preferential heating of certain elements," Klein said. "The predictions in this paper suggest that these processes are operating below the Alfvén surface, a region close to the sun that no spacecraft has visited, meaning that these preferential heating processes have never before been directly measured."

New research has found no increased risk of congenital malformations associated with treatment with radiotherapy or chemotherapy in children of fathers with testicular cancer. The study, by Yahia Al-Jebari of Lund University, Sweden and colleagues, is published in the open-access journal PLOS Medicine on June 4, 2019. It followed 4,207 children of 2,380 fathers and finds that those conceived after treatment were not at a greater risk of congenital malformations than those conceived before.

Radiotherapy and chemotherapy have been shown to cause mutations and genetic damage in animal and human sperm and there has been concern that men treated with those therapies could have an increased chance of having children with genetic disease or birth defects. Because testicular cancer affects younger men, the team were able to compare children conceived before and after their fathers received treatment.

The study data were from Swedish national birth registries, with 2 million Swedes born between 1994 and 2014. Limitations are a lack of data on frozen or donor sperm, and only a limited number of patients were treated with radiotherapy and high doses of chemotherapy. However, even for those children, no increased risk was detected.

The research does suggest a slightly raised risk associated with the fathers' testicular cancer, regardless of treatment, but that increase was small, from 3.5 to 4.4 children in every 100 born, and should not be a worry to patients.

Yahia Al-Jebari says: "Our research set out to investigate whether treatment for the most common cancer among young men leads to a higher risk of fathering a child with a birth defect and we saw no increased risk associated with cancer therapies. We did see a slightly raised risk to children of these fathers but this was only very small and was not associated with treatment given. Patients should be reassured that this is not a cause for concern."

In the online world, where incivility is all too common, new research from the McCombs School of Business at The University of Texas at Austin found that being polite is golden, at least when individuals who pose questions online get to choose the "best answer."

This "politeness bias" was uncovered by Andrew Whinston, McCombs professor of information, risk and operations management, and his collaborators and former Ph.D. students, the University of Rochester's Huaxia Rui and the University of Connecticut's Shun-Yang Lee.

They said in their paper they hoped to raise awareness about "how this type of cognitive bias could affect people's decision-making processes."

The researchers looked at how answers are rated on Stack Exchange, a highly popular network of more than 170 Q&A sites covering a broad range of topics. By analyzing more than 400,000 sets of questions and answers, they discovered that askers prefer responses written in respectful forms, even when the content isn't objectively the most useful.

"If you want to give advice to someone online, you should do it politely," says Whinston.

On the other hand, politeness doesn't seem to matter to the platform members who did not ask the original question. Those readers based their votes for best answer on more objective terms, the researchers say.

Stack Exchange rates answers to questions in two ways -- the "best answer" chosen by the questioner and the "best answer" chosen by audience votes. The researchers found that audience members were not influenced by whether the responders were polite, probably because they did not take impolite responses personally. The questioners, however, apparently did. The researchers found one notable exception to that rule of thumb. Question askers were willing to excuse an impolite answer when the responder had high ratings on Stack Exchange, based on the number of votes that person's previous answers had received.

The researchers defined impolite responses by noting the presence of certain terms, such as sentences beginning with second-person pronouns such as "you" and "your," sentences beginning with a question, and informal references to the questioner such as "dude" and "bud."

In all, they examined 770,414 answers to 422,980 questions.

Question-answering platforms should take politeness bias into account to benefit themselves and their users, the researchers write. Whinston and his co-authors recommend that Q&A platforms more prominently display the number of votes compared with the question asker's "best answer." They also recommend that websites change the name "best answer" to "asker-accepted answer" or some other neutral term to reduce the bias of labeling it the "best."

"Overall, the easier it is for users to locate high-quality content, the more valuable the (website) would be to users," the study says. Further, "it is imperative that (these websites) understand the politeness bias and its consequence to ensure effective knowledge exchange and successful commercialization. A careful design of quality assessment methods can be highly beneficial to the growth of these platforms."

Scientific research usually takes months to be published by academic journals, and once it is, many of the papers can only be read by scientists from wealthy institutes that subscribe to the journals. Over the years, there have been various attempts to make research more widely available, but most papers remain behind paywalls and scientists complain that the peer review process at journals now takes longer than ever.

In a new article publishing June 4 in the open-access journal PLOS Biology, Richard Sever and John Inglis from Cold Spring Harbor Laboratory and Mike Eisen from UC Berkeley propose a new solution to these problems, which they call Plan U (for "universal"). They call on the organizations that fund research - government agencies such as NIH and charities like the Howard Hughes Medical Institute - to require the scientists they support to post drafts of their papers on free websites called "preprint servers" before submitting them to academic journals. The value of this approach was demonstrated by arXiv (pronounced "archive"), a preprint server in the physical sciences that has been running for 28 years and hosts more than a million papers. bioRxiv (pronounced "bio-archive"), founded by Sever and Inglis in 2013, brought the culture to biology and is growing rapidly as more and more biologists realize the benefits of making their work available early.

As well as making papers available sooner--and to everyone--Plan U should speed up research itself, because other experts can immediately begin building on the work. It should also stimulate evolution of the publication system. "Because preprint servers take care of dissemination, scientific journals don't have to worry about that part and so have more freedom to experiment with how they do peer review," Sever said. Servers reduce the barrier to entry for new initiatives, he added, since they no longer have to cover the costs of hosting the papers themselves.

The majority of women who underwent lumpectomy or mastectomy surgeries for breast cancer report that the scars from those surgeries negatively affect their daily lives. Yet one-third of patients said that their physician did not tell them about surgical options that minimize scarring, according to a report published recently by the journal BMC Cancer.

Breast cancer is the second most common type of cancer worldwide, with an estimated 269,000 newly diagnosed cases and more than 42,000 deaths in the U.S. in 2019, according to the National Institutes of Health. More than 3.5 million women in the U.S. have survived breast cancer, many of whom bear scars from surgical treatments.

"After surviving the trauma of cancer, many women must still battle with the psychological and physical consequences of both a new cancer diagnosis and its treatment," said author Jennifer S. Gass, MD, FACS, chief of surgery at Women & Infants Hospital, a Care New England hospital; director of the breast fellowship at the Breast Health Center at Women & Infants; a member of the Care New England Medical Group; and clinical assistant professor at The Warren Alpert Medical School of Brown University.

"Our findings illustrate how important it is for surgeons to ensure their patients are aware of the long-term impact of cancer surgery and how it will affect their bodies. Patients should know if they might be candidates for surgical options that minimize morbidity. A surgical scar is a morbidity," said Dr. Gass.

The survey reports that two-thirds of respondents do not like the location of their scar. This scar impacted the daily lives of many women, in terms of feeling self-conscious and affecting clothing choices. Yet, one in three breast cancer patients said their physician never told them about surgical options to reduce the visibility of their scars and thus potentially the psychological and physical impact of scars.

The survey of 487 women who had undergone lumpectomy and/or mastectomy surgeries is the first peer-reviewed, nationwide study to examine the negative association of surgical scars and breast cancer survivorship, how those scars affect their lives, and whether scars matter. The survey found:

64 percent of women treated with lumpectomy-only and 67 percent of women treated with mastectomy-only reported they did not like the location of their surgical scar.

63 percent of lumpectomy respondents and 77 percent of mastectomy-only respondents feel self-conscious about their scars.

57 percent of lumpectomy-only and 66 percent of mastectomy-only patients decide not to wear certain pieces of clothing because it reveals their breast cancer surgery scars.

32 percent of lumpectomy-only respondents and 35 percent of mastectomy-only respondents stated their physician did not inform them about surgical options such as nipple-sparing mastectomy or hidden scar techniques. Of those respondents, about six in 10 stated they would have considered those options if their doctor had told them about it.

60 percent of respondents who had lumpectomy-only and 72 percent of respondents who had mastectomy-only said they did not realize before their surgery how uncomfortable their scars would make them feel when they are undressed.

Only 26 percent of lumpectomy-only respondents and 14 percent of mastectomy-only respondents reported minimal or no negative impact as a consequence of surgical scars.

Advancing dementia affects relationships between carers and those in their care

It also affects relationships between those with dementia in care and their families, and the relationship between residents

A better understanding of behaviour and behavioural change the key to sustaining good relationships

Research the first to address the impact of a wide range of behaviours

Findings welcomed by Care UK, the UK's largest independent provider of health and social care, particularly in relation to staff recruitment and retention

As dementia advances, in most cases it can change the behaviour displayed by those with the condition. Such changes in behaviour can bring strain to a wide-ranging network of relationships - from those between people with dementia and their professional carers, between those with dementia and their families, and to relationships between residents in residential care homes - which in turn can affect the delivery of care.

New research published today in the journal Dementia by researchers from the University of Chichester focuses on the effects of behavioural change due to dementia in a residential care home setting. Its findings are based on a survey of professional care-givers who shared their own experiences of the deterioration of the carer/cared-for relationship as dementia advances.

People living with dementia often experience a wide range of behavioural changes, from dramatic fluctuations in sleep patterns to problems eating, changes in mood, uncharacteristic sexual behaviour, aggression, a deterioration in interpersonal skills, self-care and temperament. The condition can also result in delusions, agitation, depression, anxiety, indifference and changes in motor behaviour.

Changes in behaviour have impact not just on the individual with dementia and those close to them - it can impact on professional care-givers. Previous research has focused primarily on aggression exhibited by the person living with dementia and its impact on family care-givers. This research breaks new ground by identifying a wide range of behaviours and examining their impact not just on family, but also on professional care-givers and other residents within the care home environment.

Professional care-giver participants in the survey identified the strain dementia-related behaviour change places on the relationship between themselves and those in their care. In their professional position they were also able to witness the deteriorating effect on inter-family relationships, and on the relationships between residents within the care home itself.

The general consensus among professional care-givers was that the deterioration of relationships with their charges was upsetting for them, and that they would welcome additional support and/or training to help them better understand the ramifications of behaviour change as the result of dementia. All recognised that a better understanding would result in achieving and sustaining good relationships.

Dr Antonina Pereira, Co-Director of the Institute of Education, Health and Social Sciences at the University of Chichester is co-author with colleague Katie Appleton of the research. She commented: "Professional care-givers have identified as part of their everyday practice an effective deterioration in relationships between themselves and residents in their care. Our findings point to the fact that professional care-givers would benefit from more intense and in-depth training, focusing on the understanding of behaviour change across the development of dementia. In our view such training should ideally place emphasis on the degenerative nature of dementia and the fact that its progression is likely to differ from person to person."

Suzanne Mumford, Lead Quality Development Manager for Approach to Care and Dementia Services at Care UK, the UK's largest independent provider of health and social care and which runs more than 100 care homes, commented: "At a time when the recruitment and retention of care and nursing staff is challenging the provision of health and social care in the UK, this research highlights the impact on professional caregivers of supporting people living with dementia with diverse and complex physical and psychological needs."

She added: "The authors discuss the importance of developing communication skills through training. Care UK's university-accredited Living Well with Dementia programme of training and coaching provides all staff with training that includes a comprehensive understanding of the feelings that drive behaviours, this helps to build connection and relationships that promote trust, respect and inclusion. A broader understanding of the emotional and psychological dependency experienced by people living with dementia and how that affects the approach of both professional and family caregivers would benefit from further research to establish whether other factors can improve connection and reduce the incidence of caregiver burnout."

With summer break and longer days ahead, parents of young teens may be wondering whether to let good sleep habits slide over the next couple of months. New research from the University of British Columbia suggests there are more benefits to a good night's sleep than simply feeling refreshed.

"Chronic, low-quality sleep was associated with poorer health outcomes among young B.C. students," said study author Annalijn Conklin, assistant professor of pharmaceutical sciences at UBC and a scientist with the Centre for Health Evaluations and Outcome Sciences. "Kids who regularly had trouble falling or staying asleep were almost two and half times as likely to report sub-optimal or less than excellent health, compared to those who did not."

The study, published in Preventive Medicine, looked at 3,104 students in British Columbia aged 13 to 17 over a period of two years.

"Even if these teens had difficulty falling asleep just one night a week, if that was a regular occurrence over two years, it really seemed to affect their overall health," added Conklin. "What was particularly interesting was that the relationship between chronic, poor-quality sleep and health outcome was stronger in the boys than it was in the girls."

However, the research found no relationship between poor health outcomes and those who chronically had less than eight hours sleep a night.

As an observational study, this research does not look into cause and effect, but the researchers say the findings signal that cumulative sleep problems matter for the health of young people.

"It shows that there's definitely a link between poor health and chronic poor-quality sleep, which may be gender-specific, and I'm looking forward to seeing more research explore that connection," said Conklin.

She added that the findings highlight the need for parents to work on the many recommendations around about sleep hygiene practices. "Other studies have specifically shown that late-night screen use and caffeine consumption have harmful consequences for falling sleep. Young people's health may benefit from parents enforcing sleep schedules and placing restrictions on screen time," Conklin said.

CLEVELAND - A novel gene therapy clinical trial at University Hospitals Seidman Cancer Center and the Case Comprehensive Cancer Center is showing promising results, garnering funding with a prestigious U01 Grant from the National Cancer Institute. The trial focuses on turning patients with a poor prognosis into those with a good prognosis.

This trial involves glioblastoma multiforme (GBM), the deadliest form of brain cancer and among the most difficult cancers to treat. The mean survival from the time of diagnosis is only about one year. In the trial's Phase 1, which focuses on assessing safety rather than clinical benefit, median survival of GBM patients was 3.5-fold the expected survival based on published modeling studies with actual data from patients with similar situations in randomized clinical trials.

A $2.7 million grant to further the gene therapy study was awarded to Andrew E. Sloan, MD, Director of the Brain Tumor & Neuro-Oncology Center and the Center of Excellence for Translational Neuro-Oncology (CETNO) at UH Cleveland Medical Center and UH Seidman Cancer Center, and Stanton Gerson, MD, Director of the Case Comprehensive Cancer Center. Results of the Phase 1 clinical trial will be shared on June 2 at the American Society of Clinical Oncology's annual meeting in Chicago.

Their trial centers on the efficacy of the chemotherapeutic agents O-benzylguanine (BG) and temozolomide (TMZ) and repair enzyme MGMT, known to be an important prognostic indicator in GBM.

Since 2005, physicians have found GBM patients fall into one of two categories. Patients whose MGMT promotor is methylated and thus don't produce much of the repair enzyme MGMT comprise the "good prognosis" group. For these patients, chemotherapy and radiation work well, and almost 50 percent of them live for two years. About 55 percent of patients, however, are unmethylated and make considerable MGMT that protects the tumor from chemotherapy. This "poor prognosis" group has a median survival of only 13.8 months.

"We began to wonder if we could convert patients from 'poor prognosis' to 'good prognosis' by inhibiting MGMT with BG," Dr. Sloan said. "BG has two different effects: 1) It disables the tumor from repairing the damage induced by chemotherapy, and 2) By poisoning the bone marrow, the BG makes the body more sensitive to the side effects of radiation therapy.

"What if we could separate those two populations - the tumor and the bone marrow - and treat them as different compartments in the body?"

This, Dr. Sloan said, led to the idea of using gene therapy to alter MGMT.

Dr. Gerson developed a mutant gene called P140K, which does not bind to BG but repairs DNA damage caused by temozolomide. He and Dr. Sloan then took hematopoietic stem cells from patients' blood through leukopheresis, genetically engineered them to produce P140K to make them resistant to chemotherapy, and then re-infused them into the patient to protect the bone marrow. This study is coordinated under a cooperative agreement with investigators at NCI with some patients treated there as well, Dr. Gerson said.

The gene therapy was notably done with a new safety-modified lentiviral vector similar to those used for CAR T cell therapy. Results to date have been promising.

"Stan Gerson has been working on MGMT for 30 years and is the world expert," Dr. Sloan says. "It turns out that GBM is the one cancer where it really makes a difference!"

The trial has progressed with very few side effects among the patients. All eligible patients tolerated at least one cycle of progressively increased dosage of chemotherapy, with five cycles of dose escalation of BG and TMZ as the median. Median survival was 3.5 times longer than expected, and the MGMT mutant was 3 to 26 times higher in peripheral blood than in untreated patients.

"This regimen was tolerable, safe, and enabled dose escalation of chemotherapy with impressive improvement in survival compared to a large set of case-matched studies," Dr. Sloan said.

Drs. Sloan and Gerson also are considering the best sequence of surgery, radiation, chemotherapy and the reinfusion of genetically engineered stem cells. The Phase I trial tested three possible sequences. Remarkably, three of five patients in one of the three cohorts not only survived three years, but had no disease recurrence after that time period. Five of the 10 patients in the trial have survived more than four times longer than expected.

These highly encouraging results convinced the NCI to fund the U01 thus driving the protocol into a multi-center Phase 2 clinical trial. In this next phase, which will open before the end of the year, Dr. Sloan said the team plans to examine interactions with the immune system and explore as well as how and why the tumor returns in some patients.

DNA replication is essential for living organisms to faithfully deliver genetic information from parental cells to daughter cells. Many proteins are assembled on the parental DNA to work as replication machineries. Among them, the proliferating cell nuclear antigen (PCNA) is a key replication protein. This ring-structured molecule encircles chromosomes, thread-like structures where DNA molecules is packed into, during DNA replication. Just like a ring on a string, PCNA-ring is tightly linked to DNA. After its landing on DNA, PCNA recruits other proteins to efficiently copy the parental DNA. PCNA's stable connection to DNA makes it an essential platform for many replication machineries.

This is, however, not the end of the story. When the DNA synthesis is complete, PCNA should be removed from the DNA to ensure a complete end of its cycling. Otherwise, the replication proteins make genomic DNA unstable that may lead to genetic mutations. How then are replication machineries cleared from DNA after DNA replication? PCNA unloading from DNA clears replication machineries from DNA after DNA replication. Although PCNA unloading is crucial for maintaining genomic stability, it has been remained unclear how PCNA is unloaded during replication termination.

Led by director Myung Kyungjae, professor Kim Hajin and Dr. Kang Sukhyun at the Center for Genomic Integrity within the Institute for Basic Science (IBS) at the Ulsan National Institute of Science and Technology (UNIST), South Korea reported that they revealed a novel molecular mechanism for the regulation of PCNA cycling during DNA replication. They found that a specific protein complex called as ATAD5-RFC-Like-Complex (ATAD5-RLC) is a PCNA-unloader. Dr. Myung's group has established in vitro reconstitution system by which PCNA loading and unloading could be monitored. They proved that ATAD5-RLC opens PCNA ring to be removed from DNA as a bona-fide PCNA unloader.

These findings, in fact come from their previous studies. Another protein complex, the Replication-Factor-C (RFC) is known to open PCNA-ring and loads it onto linear DNA molecule before DNA synthesis. Until now, scientists in the DNA replication field believed RFC also function to unload PCNA since bacterial homolog of RFC does both loading and unloading reaction. Dr. Myung's group suggested that ATAD5-RLC, having a similar structure to RFC, could be a candidate for a PCNA-unloader. This study proved biochemically that ATAD5-RLC is a bona-fide PCNA unloader. The scientists also revealed that ATAD5-RLC could unload modified PCNA, too. PCNA is modified upon replication stress to deal with DNA damages. These findings highlight the role of ATAD5-RLC as a universal sweeper of PCNA for the termination during DNA replication and repair.

The scientists also identified key motifs in ATAD5 that make the protein complex as a PCNA unloader. They revealed the mechanistic differences between PCNA loading and unloading processes. The scientists found a point mutation in a key motif in ATAD5 from melanoma patients, too. Dr. Sukhyun Kang, one of the corresponding authors of this study says, "It was crucial to functionally dissect ATAD5 and purify active ATAD5-RLC. Establishment of in vitro reconstitution system allowed us mechanistic studies for PCNA unloading."

This study provides complete understanding of PCNA cycling on replicating DNA. It has been controversial which complex is responsible for the unloading of PCNA after DNA replication and repair. The scientists show that two structurally related complexes play distinct roles in PCNA-DNA association. RFC loads PCNA to initiate DNA synthesis and ATAD5-RLC unloads PCNA to terminate DNA replication/repair. Mechanistic difference between loading and unloading of PCNA revealed by this study gives us conceptual advance to understand DNA replication. Since PCNA unloading is closely linked to chromatin assembly, this study will be the basis of future studies for the relationship between replication termination and maintenance of epigenetic information.

"This is a major progress to understand regulatory mechanism for replication termination process. Since uncontrolled disassembly of replication machineries causes genomic instability that may result in cellular transformation, our study will be beneficial to develop strategies for cancer treatment" explains director Myung.

Researchers at Tokyo Institute of Technology (Tokyo Tech) and NEC Corporation, Japan, present a 39 GHz transceiver with built-in calibration for fifth-generation (5G) applications. The advantages to be gained include better quality communications as well as cost-effective scalability.

A team of more than 20 researchers at Tokyo Tech and NEC Corporation has successfully demonstrated a 39 GHz transceiver that could be used in the next wave of 5G wireless equipment including base stations, smartphones, tablets and Internet-of-Things (IoT) applications.

Although research groups including the current team have until now largely focused on developing 28 GHz systems, 39 GHz will be another important frequency band for realizing 5G in many parts of the world.

The new transceiver is based on a 64-element (4 x 16) phased-array[1] design. Its built-in gain phase calibration means that it can improve beamforming[2] accuracy, and thereby reduce undesired radiation and boost signal strength.

Fabricated in a standard 65-nanometer CMOS[3] process, the transceiver's low-cost silicon-based components make it ideal for mass production -- a key consideration for accelerated deployment of 5G technologies.

The researchers showed that the built-in calibration has a very low root-mean-square (RMS) phase error of 0.08°. This figure is an order of magnitude lower than previous comparable results. While transceivers developed to date typically suffer from high gain variation of more than 1 dB, the new model has a maximum gain variation of just 0.04 dB over the full 360? tuning range.

"We were surprised to achieve such a low gain variation when actually using the calibration based on our local-oscillator (LO) phase-shifting approach," says project leader, Kenichi Okada of Tokyo Tech.

In addition, the transceiver has a maximum equivalent isotropic radiated power (EIRP)[4] of 53 dBm. This is an impressive indication of the output power of the 64 antennas, the researchers say, particularly for low-cost CMOS implementation.

Indoor testing (under anechoic chamber conditions[5]), which involved a one-meter, over-the-air measurement, demonstrated that the transceiver supports wireless transmission of a 400 MHz signal with 64QAM.

"By increasing the array scale, we can achieve greater communication distance," Okada says. "The challenge will be to develop the transceiver for use in smartphones and base stations for 5G and beyond."

The work is being presented at the 2019 IEEE Radio Frequency Integrated Circuits Symposium (RFIC) in Boston, Massachusetts, US, as part of the morning session (Session RTu2E) to be held on 4 June 2019. The paper of this work "A 39 GHz 64-Element Phased-Array CMOS Transceiver with Built-in Calibration" by Yun Wang et al., receives the best student paper award.

The fight against superbugs could be helped by the discovery of a potential therapy based on the body's natural immune defences.

Scientists have found that a molecule produced by the body - called LL-37 - changes the way cells behave when they are invaded by bacteria.

The molecule acts like a fire alarm, experts say, warning the body's immune system of the infection and the need for urgent action.

The team, from the University of Edinburgh's Centre for Inflammation Research, focused on lung diseases caused by bacterial infections, which are a major cause of death worldwide.

These infections are increasingly resistant to antibiotics, making them difficult to treat.

Previous studies with mice found that LL-37 instructs cells in an infected lung to call in specialised cells, known as neutrophils, which can destroy bacterial threats.

In tests on human lung cells, researchers found that LL-37 specifically targets infected cells, revealing the danger and producing a signal that summons the neutrophils.

At the same time, this flood of LL-37 into the infected cells causes them to self-destruct, removing the threat to other healthy cells before the bacteria can grow and spread.

Experts say this discovery could lead to new approaches to treat these multi-drug resistant infections.

Dr Donald J. Davidson from the MRC Centre for Inflammation Research said: "Our search for alternative and complementary treatments for antibiotic-resistant infections is becoming ever more urgent. Trying to boost the best of the human body's effective natural defences, like this, may prove to be an important part of our future solutions."

A new study conducted by researchers at the Center for Injury Research and Policy of the Abigail Wexner Research Institute at Nationwide Children's Hospital and the Central Ohio Poison Center investigated trends in calls to poison control centers across the country for exposure to liquid laundry detergent packets. It found a modest decrease in calls for children younger than 6 years of age following adoption of a 2015 product safety standard but an increase in calls for older children and adults.

The study, published online today in Pediatrics, found that from January 2012 through December 2017, U.S. poison control centers received 72,947 calls related to liquid laundry detergent packet exposures - during 2017, there was an average of one call about every 42 minutes. Most exposures involved children younger than 6 years (91.7%), a single substance (97.5%), or occurred at a residence (98.5%). Approximately 6.4% of single-substance exposures resulted in serious medical outcomes. During the study period, there were eight deaths associated with the ingestion of laundry detergent packets as single-substance exposures. Two of these involved children 7 and 16 months old. The other six deaths were among adults age 43 years and older with a history of dementia, Alzheimer's disease, or developmental disability.

In an effort to reduce unintentional exposures to the contents of liquid laundry detergent packets, ASTM published a voluntary Standard Safety Specification for Liquid Laundry Packets in 2015, but some experts feel it did not go far enough. The leading U.S. manufacturer of laundry detergent packets began implementing a series of changes to the product and its packaging to reduce child exposures in 2013. The American Academy of Pediatrics (AAP), Prevent Child Injury, and other organizations have conducted public awareness campaigns about the hazards of laundry detergent packets for young children. This study investigated the effect of these safety interventions and found that the number and rate of exposures among children younger than 6 years declined by only 18% following adoption of the ASTM safety standard in 2015.

"The voluntary standard, public awareness campaigns, and product and packaging changes to-date are good first steps, but the numbers are still unacceptably high," said Gary Smith, MD, DrPH, senior author of the study and director of the Center for Injury Research and Policy at Nationwide Children's Hospital. "We can do better." One reason for the less-than-expected decline in exposures among young children is likely because the voluntary safety standard permits manufacturers to meet the requirement for child resistant containers in six different ways rather than requiring them to conform to the Poison Prevention Packaging Act (PPPA) of 1970, which has been shown to be highly effective in preventing child access to poisons. "Requiring that all liquid laundry detergent packet packaging be PPPA-compliant would be an important next step in reducing child access to these products," said Dr. Smith. "In addition, each laundry packet should be individually wrapped with child-resistant packaging, which would provide important layers of protection for this highly toxic product."

Liquid laundry detergent packets are more toxic than traditional liquid and powder laundry detergent. The reasons for this increased toxicity are not completely understood, and further research is needed to determine how to make packet contents less toxic. Such reformulation would reduce the severity of exposures to liquid laundry detergent packets.

Pediatricians and other healthcare providers should continue to counsel patients and their families about the hazards of laundry detergent packet exposures and the importance of safe storage practices. Experts recommend that caregivers to children younger than 6 years old and adults with a history of dementia, Alzheimer's disease, or developmental disability use traditional laundry detergent instead of packets.

"Many families don't realize how toxic these highly concentrated laundry detergent packets are," said Henry Spiller, MS, D.ABAT, co-author of the study and director of the Central Ohio Poison Center. "Use traditional laundry detergent when you have young children or vulnerable adults in your home. It isn't worth the risk when there is a safer and effective alternative available."

Data for this study were obtained from the National Poison Data System, which is maintained by the American Association of Poison Control Centers (AAPCC). The AAPCC receives data on calls to regional poison control centers that serve the US and its territories. Poison control centers receive phone calls through the Poison Help Line and document information about the product involved, route of exposure, individual exposed, medical outcome, and other data.

AUGUSTA, Ga. (June 3, 2019) - Nearly half the amplitude typically used in standard electroconvulsive therapy (ECT) seems to be effective at treating suicidal thoughts, investigators report.

The small, randomized pilot study, the first to look at lower-amp ECT for suicidal ideation in patients with major depressive disorder and bipolar depression, included a total of seven patients, three treated with low amplitude ECT at 500 milliamps, and four with a standard amplitude of 900 milliamps, Medical College of Georgia investigators report in the journal Brain Sciences.

They have previously shown that lower current amplitude has less cognitive and memory side effects than the standard amplitude ECT.

"All clinical outcomes were similar," says Dr. Nagy A. Youssef, psychiatrist specializing in ECT in the MCG Department of Psychiatry and Health Behavior at Augusta University and the principal investigator of the new study.

Patients receiving the low amp ECT had relief from their suicidal thoughts by the third ECT session, while it took an average of four sessions for the standard group. Low amplitude ECT also meant patients woke up from their treatment in just a few minutes, rather than about 15 minutes -- a positive predictor of cognitive side effects from therapy -- with essentially no impact on memory or cognition.

Patients receiving low amp ECT also seemed to get a higher degree of relief from their suicidal thoughts, with higher scores from baseline to after treatment than with standard amp ECT -- 5.1 compared to 3.0 -- based on a 10-item questionnaire used to measure depression severity and suicidal thoughts specifically.

The investigators had hypothesized they would see similar improvement in magnitude and speed of remission in both groups based on their earlier work. Youssef notes that many depression centers in the brain are more superficial than memory centers, so higher amplitude is not necessary to reach the depression areas. Lower amplitude will also spare the deeper memory areas. He has worked with bioengineers at Duke University to adjust other parameters, like the frequency of stimulation, to make low amplitude more effective.

Next steps include a multicenter trial that compares the approaches in a larger number of patients and follows patients for longer periods, he says.

"We need to do larger studies with more patients as this approach seems very promising," says Youssef, first author on the paper who, over the past 10 years, has done some of the first exploration of lower amplitude ECT in animal and computer models as well as humans.

Suicide is a leading cause of death in the United States, according to the Centers for Disease Control and Prevention, and it's on the increase. Depressive episodes, as part of major depressive disorder, or as part of bipolar disorder or schizoaffective disorder, are a major risk factor for suicide, particularly for those with treatment-resistant depression, which is about one-third of patients with depression, Youssef says.

There is already good evidence that ECT is an effective treatment for depression. For example, the multicenter PRIDE study, funded by the National Institutes of Health, indicated that ECT should be widely used to get and keep more elderly individuals with severe depression in remission.

Along with the stigma still associated with ECT, another reason ECT is not more widely used for depression or suicidal thoughts is concern about the impact on cognition, a primary side effect of standard amplitude ECT, Youssef says.

An earlier study led by Yousef and Emad Sidhom, psychiatry fellow at the psychiatric facility Behman Hospital in Cairo, Egypt, provided some of the first evidence that lowering the amplitude helped with cognitive concern.

The 2017 study published in the Journal of Affective Disorders looked at 22 patients with treatment resistant depression or psychotic disorders, all of whom received low amp ECT. It found patients experienced seizures under full anesthesia and muscle relaxant -- in this case a controlled surge of electrical activity in the brain that is considered necessary for ECT to work -- had their depression relieved and experienced less cognitive impact than with traditional amp ECT. It appeared to be the first published study in humans of this lower amp approach in depression.

Youssef notes that the induction course of ECT, particularly when electrodes are placed on both sides of the brain, increases the potential impact on memory. However, ECT to just one side of the brain, which was used in both arms of the current study, has been found to produce less cognitive side effects.

The right side of the brain is most commonly used for one-sided treatment because right handed people -- who make up some 70-95% of the world's population -- as well as about 85% of people who are left-handed have centers like speech and writing in the left brain, which physicians don't want to stimulate, Youssef says. In the comparatively rare cases when a simple test indicates that those centers are on the right side, they focus therapy on the left side, he says.

ECT-related memory loss typically resolves with time or spacing of treatments.

Although just how ECT works as an antidepressant and antipsychotic is not well understood, it's considered analogous to how an electric shock can restart a still or erratically beating heart and somehow reset its rhythm, Youssef says. Often patients have tried and failed several medications and psychotherapy and an acute course of ECT can help abort a severe psychotic or depressive episode. Sometimes medications alone will then start to work when symptoms are ameliorated or in remission, however a small percentage of patients will benefit from a lifetime of maintenance ECT, he says.

We all have different thresholds for inducing seizures and all patients in the current study did experience seizures at the lower amplitude, Youssef says. He notes that seizures induced by ECT are not the same as a grand mal seizure induced by abnormal electric activity in the brain rather it's one of short duration, with controlled medical conditions while a patient is under anesthesia.

The bigger the brain in relation to body size, the more intelligent a living organism is. This means that mammalian species with large brains are smarter than small-brained mammals. However, developing a large brain comes at a price: An infant expends around two-thirds of its energy alone on supplying nourishment to its brain. That huge amount of energy must be continually available in the form of milk and, later on, through the intake of food. The females of many large-brained animal species cannot bear the energetic costs of rearing offspring on their own - they are reliant on additional help.

Fathers help dependably

Previously, it was generally assumed that it is immaterial whether it is the father or other members of the group who assist the mother in caring for offspring. However, evolutionary biologist Sandra Heldstab and her colleagues Karin Isler, Judith Burkart and Carel van Schaik from the University of Zurich's Department of Anthropology have now demonstrated for the first time that it very well does matter who helps the mother. Animal species with paternal care of offspring are particularly able to energetically afford bigger brains. Help from other group members is far less essential to the evolution of a large brain. In their study, the researchers compared brain sizes and the extent and frequency of paternal and alloparental care in around 480 mammalian species.

"Fathers help consistently and dependably with the rearing of offspring, whereas assistance from other group members, such as elder siblings for instance, is far less reliable," Sandra Heldstab explains. For example, in the case of wolves and African wild dogs - two mammal species with large brains -, elder siblings often help out less, and they look out for themselves first when food is scarce. Sometimes they even steal the prey that parents bring for the infants. The father, in contrast, actually steps up his willingness to help his young offspring when environmental conditions worsen.

Bigger brains or bigger litters

In the case of other species like meerkats and prairie voles, for instance, elder siblings often defect to a different group when they reach puberty and, unlike the father, are no longer available to help the mother. Moreover, the quality of the paternal help is usually superior to help provided by other group members, who are often young and inexperienced. "A female cannot energetically afford offspring with large brains unless she can rely on help, and such dependable help only comes from the father," Heldstab says.

If the assistance that the female receives for rearing her young is inconsistent, evolution takes an alternative path. In mammalian species that fit this bill - such as lions and red-ruffed lemurs for example -, mothers do not give birth to few offspring with large brains, but to many with small brains. If there is plenty of help in caring for the young, the entire litter survives. If the female receives little support, some of the young die. This is evolution's way of making certain that at least some of the young survive even in the event of scant help and ensuring that the female doesn't needlessly invest energy in an offspring with a large brain that will die in the absence of dependable helpers. The study demonstrates once more that only a stable and dependable supply of energy - procured through paternal help, for instance - enables a large brain to develop in the course of evolution.

Humans are the exception

Humans are unique in this respect: Paternal assistance in child rearing is very reliable, but so is childcare help from other relatives and non-relatives. This circumstance enabled humans to develop the largest brain relative to body size in the animal kingdom and nonetheless to considerably shorten the time span between births compared to that for our closest relatives, apes. "In the world of mammals, only help from fathers is dependable. We humans, though, fortunately can also count on help from others," Sandra Heldstab says.