They published their results on Jan. 1 in Bioorganic & Medicinal Chemistry.

“Lankacidins have potential antitumor agents, however, their structural modification has somewhat problem due to the presence of complex bicyclic ring in lankacidin antibiotics,” said paper author Kenji Arakawa, associate professor at Hiroshima University’s Graduate School of Integrated Sciences for Life. “Structural modification of lankacidin C, as a mother compound, would be an excellent starting point for enhancing antitumor activity through computational prediction.”

The researchers preliminarily assessed how various components of lankacidin-group antibiotics may contribute to its antitumor activity using a computational model, finding that a structural ring of carbon atoms, called the delta-lactone ring, may not be essential. According to Arakawa, the implication was striking, since the ability to structurally modify lankacidins has been limited by the presence of the delta-lactone ring.

“In this study, we synthesized lankacyclinone C, a novel lankacidin C variant lacking the delta-lactone ring,” Arakawa said. “In doing so, we solved one major issue of structural function in the lankacidin skeleton, the bicyclic structure of the delta-lactone ring, for antitumor activity.”

They used a protein called Orf23 to convert the bicyclic structure with the delta-lactone ring to a monocyclic version. A computational model predicted that the resulting lankacyclinone C, with a simplified ring, would still prove cytotoxic to target cancer cells. Experimental results supported the prediction.

“Rather than bicyclic lankacidins, structurally simple and flexible monocyclic lankacidins may be better substrates for further structural redesigning to improve antitumor activity,” Arakawa said.

According to Arakawa, the researchers plan to further investigate the rational design of molecular compounds with the goal of creating the ultimate antitumor agents.

Other contributors include Rukman Muslimin, Natsumi Nishiura and Aiko Teshima, Unit of Biotechnology, Division of Biological and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, Japan; Kiep Minh Do, Takeshi Kodama and Hiroyuki Morita, Institute of Natural Medicine, University of Toyama, Japan; Cody Wayne Lewis and Gordon Chan, Department of Oncology, Cross Cancer Institute and Cancer Researcher Institute of Northern Alberta, University of Alberta, Canada; and Ahmed Taha Ayoub, Medicinal Chemistry Department, Heliopolis University, Egypt.

Arakawa, Nishiura and Teshima are also affiliated with the Hiroshima Research Center for Healthy Aging, Hiroshima University.

The Japan Society for the Promotion of Science, the Ministry of Scientific Research/Science and Technology Development Fund, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Izaak Walton Killam Memorial Scholarship, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health and the Indonesia Endowment Fund for Education supported this work.

One hundred thousand knee replacement surgeries are carried out in the UK every year. Most of these operations take place to treat pain related to osteoarthritis. Unfortunately, each year, around 20,000 people who have knee replacement surgery to relieve their pain find that they have moderate to severe pain three months or longer after their operation, which impacts on their everyday lives.

The study found the STAR care pathway (Support and Treatment After joint Replacement) reduces pain severity, the amount pain interferes with people’s lives and is cost-effective. The new treatment could potentially save the NHS up to £14 million per year through reduced inpatient admissions.

The study found patients who received the STAR care pathway had:

• Less pain severity and impact on daily life at both six and 12 months after treatment (nine and 15 months after surgery)
• Half the number of hospital re-admissions
• Reduced length of hospital stay for any inpatient admissions three months after surgery
• Less unpaid time off work

The aim of the five-year STAR programme was to find ways to improve the care and support that people with ongoing pain receive. The programme, funded by the National Institute for Health Research (NIHR), designed and tested a new treatment in a randomised controlled trial in eight UK hospitals.

The programme looked at how likely patients are to get ongoing knee pain after their operation and discovered why patients don’t seek help. The research team developed a new treatment — a care pathway — for patients and compared how patients did on the STAR care pathway when compared with a control group who had the usual care.

STAR care pathway:

• Three months after surgery patients attended an hour-long clinic, ran by specially trained health care professionals
• Detailed pain questionnaires were filled out and X-rays were taken as well as a blood test for infection. If needed patients were referred for further ongoing treatment
• Patients received up to six ‘phone calls over the next 12 months, making sure they had their referral, and to check how they were doing

Rachael Gooberman-Hill, lead researcher for the STAR programme, Professor of Health and Anthropology and Director of Bristol’s Elizabeth Blackwell Institute, said: “People have a knee replacement to relieve their pain and it’s immensely disappointing if they find that they have long-term pain afterwards. Unfortunately, one in five people who have knee replacement have long-term pain afterwards — that is around 20,000 people each year in the UK alone.

“As a research team we wanted to do something that would help. We found that our new STAR care pathway had a positive impact on people’s pain. People who had long-term pain after their knee replacement and who were given STAR had less pain and the pain interfered less with their lives one year later. People told us that STAR helped them to feel supported, to find out more about their pain and STAR meant that they were able to get further treatment that was tailored to their pain. We are enormously pleased with our research findings because it should make a real difference to people who find that they have pain after their knee replacement.”

Brenig, a participant on the STAR trial, explained: “As part of the STAR trial, you have tailored physiotherapy appointments. At my three-month review with a STAR physiotherapist, I was having a problem not being able to straighten my leg out. She gave me some simple exercises, which worked and straightened the leg out. Occasionally I have problems at the back of the knee, then I do the exercises and it goes back to normal. So that was a very positive side of what we actually did.

“I felt that being part of the STAR trial gave me access to a specialist physiotherapist. Her knowledge was far, far superior and specific to my issue. Some mornings I get up and feel on top of the world and then the following day I have leg pain. Eventually you get to accept it, but doing the exercises helps.”

The study has benefited greatly from Bristol’s Musculoskeletal Research Unit’s patient involvement group, PEP-R (Patient Experience Partnership in Research) who worked closely with the STAR research team to develop the design of the programme.

Dr Vikki Wylde, Associate Professor in Musculoskeletal Health at Bristol Medical School (THS), and co-author, added: “The new STAR care pathway provides benefit to people with pain at three months after knee replacement, but we still need more research to understand how we could prevent people from developing this pain. High-quality research to pre-operatively identify patients at high risk of developing pain after their operation is needed. These patients could be offered treatments to increase their chance of a good outcome after knee replacement.”

Nick Howells, Consultant Orthopaedic Knee Surgeon at NBT and Honorary Senior Lecturer at Bristol Medical School: THS, continued: “Knee replacement surgery is a great operation that changes the lives of many people suffering with knee osteoarthritis, improving pain, function and quality of life, however, a proportion of people are left with ongoing pain. To have developed an intervention which has been shown to make a difference for some of these people is really satisfying for our team and a great step forward in treatment.

“We have now successfully introduced the STAR care pathway into our NHS clinical care pathway at North Bristol and hope it will be adopted in other centres across the NHS in the future.”

The intranasal vaccine contributed to multifaceted immune responses, leading to robust cross protection against influenza in mice. The vaccine consists of PEI-HA/CpG nanoparticles. PEI (polyethyleneimine), a robust and versatile delivery system, can simultaneously carry antigens (hemagglutinin, HA) that induce an immune response in the body, and adjuvants (CpG) that enhance the body’s immune response to an antigen for optimal immunoenhancement.

These comprehensive immune responses and cross protection were long lasting, exhibiting defense from influenza virus over six months after immunization. The findings are published in the journal ACS Applied Materials & Interfaces.

Intranasal vaccination is an ideal approach for infectious respiratory diseases such as influenza. Seasonal influenza vaccines generally induce narrow immune responses that rapidly decline, which leaves populations vulnerable to novel influenza strains. Advancements in influenza vaccine technology are needed to protect against a wide range of influenza viruses. Intranasal vaccination can improve local mucosal immune responses by preventing influenza infection at the portal of virus entry.

In the influenza virus, HA is a protein that plays a crucial role in the early stages of virus infection. Influenza HA has a head region and stalk region. Current influenza vaccines elicit immune responses against the HA head, but this head region is highly changeable and accounts for lowered efficiency against different strains. The HA stalk region is more conservative across different strains of influenza viruses.

Protein antigens that are administered intranasally are usually less able to provoke an immune response, so adjuvants are needed to have highly efficient intranasal vaccines. Adjuvants, such as CpG, can enhance and manipulate immune responses, thus improving the potency and breadth of protection.

“The PEI-HA/CpG nanoparticles show good potential as a cross-protective influenza vaccine candidate,” said Dr. Baozhong Wang, corresponding author of the study and a professor in the Institute for Biomedical Sciences at Georgia State. “The combination of PEI and CpG in the PEI-HA/CpG nanoparticle group contributed to the multifaceted immune responses, leading to vigorous cross protection. The incorporation of CpG and antigens into the same nanoparticle enhanced cellular immune responses.

“Our results revealed that the nanoparticles significantly enhanced HA immunogenicity, or the ability to provoke an immune response, providing cross protection against different influenza virus strains. The conserved HA stalk region induced substantial antibodies in the nanoparticle immunization groups.”

“Nanoparticle platforms have shown intriguing characteristics and great potentials in the development of next-generation cross-protective influenza vaccines,” said Dr. Chunhong Dong, the first author of the study and a postdoctoral fellow in the Institute for Biomedical Sciences. “However, challenges exist to the successful research and development of nanoparticle vaccines. Though no apparent adverse effects were observed in the study, a more comprehensive safety evaluation of the nanoparticle adjuvant system is needed before clinical trials.”

Co-authors of the study include Baozhong Wang, Chunhong Dong (first author), Ye Wang, Wandi Zhu, Yao Ma, Joo Kim, Lai Wei and Gilbert X. Gonzalez.

The study was funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health.

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In a new study published in the journal Biogeosciences, a team of researchers from Dalhousie University in Halifax, Canada and the GEOMAR Helmholtz Centre for Ocean Research Kiel in Germany have now, for the first time, measured the flow of oxygen into the deep ocean interior that is carried by these deep currents. It is the oceanographic equivalent of measuring oxygen transport in our bodies through the main artery or aorta.

From one sea to many oceans

Jannes Koelling, lead author of the study, explains, “We wanted to know how much of the oxygen that is breathed in each winter actually makes it into the deep, fast-flowing currents that transport it across the globe.”

The deep mixing of oxygen in the central Labrador Sea is only a first step in the deep ocean’s life support system. Deep, boundary currents then distribute the oxygen to the rest of the Atlantic Ocean and beyond. This way, oxygen that is ‘inhaled’ in the Labrador Sea can support deep ocean life off Antarctica and even in the Pacific and Indian Oceans.

Koelling explained, “The newly inhaled oxygen was clearly noticeable as a pulse of high oxygen concentration that passed our sensors between March and August.”

Compelling insights over two years

The team unravelled the connection between oxygen uptake from the atmosphere and its onward transport into the interior using dissolved oxygen sensors that were mounted for two years on anchored cables which reached from the seafloor to near the surface. The sensors were deployed at depths of about 600m, where the scientists expected water to propagate from the deep mixing region in the centre of the Labrador Sea (the lung).

The new measurements revealed that about half of the oxygen taken up from the atmosphere in the central Labrador Sea in winter was injected into the deep boundary current over the following 5 months. While some of the remaining oxygen may have been consumed locally by fish and other organisms, the bulk most likely took an alternative route out of the deep mixing region.

Findings could impact the climate model

The study and the new ability to monitor oxygen transport becomes highly relevant, given that climate model projections suggest an increased supply of freshwater — from melting glaciers and other climate-changes in the Arctic — could reduce the depth of wintertime mixing in the Labrador Sea in coming decades. This would make the Labrador Sea’s ‘breathing’ shallower and reduce the life-supporting supply of oxygen to the deep sea.

“This is an example of how monitoring enabled by the latest ocean technology can help us fill in knowledge gaps in this important region,” says Dariia Atamanchuk, who leads the oxygen programme at Dalhousie.

Koelling concludes: “The circulation of the Labrador Sea is complex, and we’ve only focused, so far, on the most direct export route. Some oxygen-rich water may be transported eastwards, instead of to the southwest, and it may enter the boundary current off Greenland before returning southwards, over a longer time-period.” These other pathways, shown as dashed lines in the map, are being investigated with further studies, using additional oxygen sensors mounted on more moorings.

The new findings are the result of a collaboration supported by the Ocean Frontier Institute, a transatlantic research organisation that connects researchers from several major institutions in Canada, Europe and the USA in a common focus on the climate-sensitive Northwest Atlantic Ocean.

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J Calvin Coffey, Foundation Chair of Surgery at UL’s School of Medicine in Ireland, whose major discovery led to the reclassification of the mesentery as a new organ in 2016, has published new research on the makeup and structure of the abdomen.

In a research paper published in the Nature Portfolio journal Communications Biology, Professor Coffey’s team has detailed the development and structure of the mesentery. In doing this, they uncovered a new order by which all contents of the abdomen are organised or arranged — or the “fundamental order of the abdomen.”

The importance of these findings on the mesentery and the impact these have on our understanding of the abdomen have been further explained in a review article just published in the Lancet Gastroenterology and Hepatology.

“Since 2016, Kevin Byrnes, Dara Walsh and members of the team been looking at the development and structure of the mesentery,” explained Professor Coffey, who is also Head of Department of Surgery, Consultant General and Colorectal Surgeon at UL Hospitals Group.

“We showed how the mesentery is a single and continuous organ in and on which all abdominal digestive organs develop and then remain connected to throughout life.

“These findings revealed a simplicity in the abdomen that was not apparent in conventional descriptions of anatomy,” he explained.

In an international collaboration, Professor Coffey’s team used a variety of state of the art techniques to clarify how the mesentery develops and the shape it has in adults.

The conclusion of the work revealed that the organisation of the abdomen has a remarkably simple design. This design is summarised in a description called the ‘Mesenteric Model of Abdominal Anatomy’.

“The abdomen is not the dauntingly complex collection of separate organs it was previously thought to be,” said Professor Coffey.

“Instead, all digestive organs are neatly packaged and arranged by the mesentery into a single digestive engine. That simplicity lay hidden until clarification of the nature of the mesentery.”

The model itself was described by the team in the most recent edition of Gray’s Anatomy. The supportive evidence was published in Communications Biology and the clinical importance was explained in the review in The Lancet Gastroenterology and Hepatology.

“The most important finding here was the discovery of the fundamental order of the abdomen. At the foundation level, all contents of the abdomen are simply organised into one of two compartments,” explained Professor Coffey.

“The fundamental order of any structure is of considerable importance, in particular when it comes to diagnosing patients with illness and treating their disease. The fundamental order is the foundation from which all science launches and clinical practice is based.

“The organisational simplicity of the abdomen now immediately explains the behaviours of viral and bacterial infections, cancer, inflammatory bowel disease, obesity, diabetes and many others,” he added.

Better understanding of the mesentery and its functions has already led to improvements in surgery and the new research builds on those advances. There are also exciting areas for future investigation, Professor Coffey outlined.

“Patients are already benefiting from what we now call mesenteric-based approaches to the diagnosis and treatment of most abdominal conditions. The Mesenteric Model of Abdominal Anatomy — or the description of the order of the abdomen — is being incorporated into numerous reference curricula at this moment,” he said.

“Regarding the future, it is being argued that we are seeing a paradigmatic shift from old to new order. Already, intriguing questions are emerging that we can call ‘legitimate or admissible’ in the strictest scientific sense. Science can approach numerous questions in a new light. Clinicians can design diagnostic and treatment approaches based on a new foundation,” Professor Coffey concluded.