Researchers found similar oral bacterial compositions among patients with early rheumatoid arthritis and those at risk of developing the disease, compared with healthy individuals who were not at risk.
The oral cavity is host to approximately 800 identified species of bacteria. The periodontum, ie the tissue surrounding the tooth, can become inflamed because of a complex interaction of bacterial infection and the body’s response, modified by behavioural factors such as smoking, result in periodontal disease. Periodontal disease has been shown to be caused by certain diseases and medical conditions, and may also cause them. Periodontitis is prevalent among rheumatoid arthritis patients.
The researchers recruited three groups of 50 participants each: early rheumatoid arthritis patients, at‐risk individuals, and healthy controls. They were given periodontal examinations and assessed for bleeding on probing, pocket probing depth, and periodontal inflamed surface area. The microbial composition of subgingival dental plaque, saliva, and tongue coating was assessed using 16S rDNA amplicon sequencing, and compared between groups.
They found that patients and at-risk individuals had an increased relative abundance of potentially pro- inflammatory bacteria in the mouth, suggestive of a possible relationship between oral microbes and rheumatoid arthritis.
“Prevotella and Veillonella–both gram-negative anaerobes–were at higher relative abundance in saliva, and Veillonella was also at higher relative abundance in tongue coating, of both early rheumatoid arthritis patients and at-risk individuals compared to healthy controls,” the authors wrote.
The findings were published in Arthritis & Rheumatology.
Journal information: Kroese, J. M., et al. (2021) The oral microbiome in early rheumatoid arthritis patients and individuals at risk differs from healthy controls. Arthritis & Rheumatology. doi.org/10.1002/art.41780.
Pioneering new research has charted the unique genetic profile of the skeleton’s ‘master regulator’ cells, known as osteocytes.
The study led by the Garvan Institute of Medical Research was published in Nature Communications. The study describes the genes that are switched on or off in osteocytes, a multifunctional type of bone cell that regulates how bone material is grown or broken down in order to maintain healthy skeletons.
“This new information provides a kind of genetic shortlist we can look to when diagnosing bone diseases that have a genetic component,” said the study’s first author Dr Scott Youlten, Research Officer in the Bone Biology Lab. “Identifying this unique genetic pattern will also help us find new therapies for bone disease and better understand the impacts of current therapies on the skeleton.”
Far from static, the skeleton is a highly dynamic structure that is constantly remodelled throughout a person’s life. Though osteocytes are the most common cell type in bone, they have been hard to study as they are embedded within the skeleton’s hard mineral structure.
Osteocytes form a network inside bones on a scale and complexity which mirrors the neurons in the brain (42 billion osteocytes with over 23 trillion connections between them), which monitors bone health and responds to ageing and damage by signalling other cells to either add more bone or break down old bone. Osteoporosis, rare genetic skeletal disorders and other bone diseases arise from an imbalance in these processes.
To understand what genes are involved in controlling bone build-up or breakdown, the researchers isolated bone samples from different skeletal sites of experimental models in order to measure the average gene activity in osteocytes. In so doing, they found an osteocyte ‘signature’ of 1239 genes that are switched on. Of these genes, 77% had no previously known role in the skeleton, and many were completely novel and unique to osteocytes.
“Many of the genes we saw enriched in osteocytes are also found in neurons, which is interesting given these cells share similar physical characteristics and may suggest they are more closely related than we previously thought,” explained Dr Youlten.
Comparing the osteocyte signature genes with human genetic association studies of osteoporosis could identify new genes that may be associated with susceptibility to this common skeleton disease. Additionally, a number of these osteocyte genes were also shown to be responsible for rare bone diseases.
“Mapping the osteocyte transcriptome could help clinicians and researchers more easily establish whether a rare bone disease has a genetic cause, by looking through the ‘shortlist’ of genes known to play an active role in controlling the skeleton,” said Dr Youlten.
Co-senior author Professor Peter Croucher, Deputy Director of the Garvan Institute and Head of the Bone Biology Lab, said that “the osteocyte transcriptome map gives researchers a picture of the whole landscape of genes that are switched on in osteocytes for the first time, rather than just a small glimpse”.
“The majority of genes that we’ve found to be active within osteocytes had no previously known role in bones. This discovery will help us understand what controls the skeleton, which genes are important in rare and common skeletal diseases and help us identify new treatments that can stop development of bone disease and also restore lost bone.”
India postponed exams for trainee doctors and nurses on Monday, freeing them up to fight the world’s biggest surge in COVID infections, as the health system buckles under the weight of new cases, and a lack of beds and oxygen.
The total number of infections so far rose to just short of 20 million, propelled by a 12th straight day of more than 300 000 new cases.
Actual numbers in India could be five to 10 times higher than those reported, according to medical exports.
Hospitals have been overloaded, oxygen has run short, and morgues and crematoriums have struggled with the number of corpses. “Every time we have to struggle to get our quota of our oxygen cylinders,” said BH Narayan Rao, a district official in the southern town of Chamarajanagar, where 24 COVID patients died, some suspected from lack of oxygen.
“It’s a day-to-day fight,” added Rao, describing the struggle for supplies.
In many cases, volunteer groups have come to the rescue. Outside a temple in India’s capital, New Delhi, Sikh volunteers provided oxygen to patients lying on benches inside makeshift tents, hooked up to a giant cylinder. A new patient would come in every 20 minutes.
“No one should die because of a lack of oxygen. It’s a small thing otherwise, but nowadays, it is the one thing every one needs,” Gurpreet Singh Rummy, who runs the service, told Reuters.
Offering a glimmer of hope, the country’s health ministry said that positive cases relative to the number of tests fell on Monday for the first time since at least April 15, and modelling shows that the virus could peak on Wednesday.
While 11 states and regions have put movement curbs in place to stem transmissions, Prime Minister Narendra Modi’s government, widely criticised for allowing the crisis to spin out of control, is reluctant to announce a national lockdown, concerned about the economic impact.
“In my opinion, only a national stay at home order and declaring medical emergency will help to address the current healthcare needs,” Bhramar Mukherjee, an epidemiologist with the University of Michigan, said on Twitter.
As medical facilities near collapse, the government postponed an exam for doctors and nurses to free up some to join in the COVID fight, it said in a statement.
Prime Minister Modi has provoked criticism for not acting earlier to limit the spread and for allowing millions of people, mostly without masks, to attend religious festivals and political rallies during March and April.
In early March, a forum of government scientific advisers warned officials of a new and more contagious variant of the coronavirus taking hold, five of its members told Reuters.
Four of the scientists said in spite of the warning, the federal government did not try and impose strict curbs.
Meanwhile, in response to India’s crisis, aid has poured in. On Sunday, the UK government said it will send another 1000 ventilators to India.
Several nations have shut their borders to Indian arrival as the Indian COVID variant has now reached at least 17 countries including the UK, Iran and Switzerland.
Although long hours in the lab are standard, some young cancer researchers have told BBC’s Radio 1 Newsbeat that, in order to continue their work, the pandemic is forcing them to work longer, harder days with no pay.
Many relished the easing of COVID rules in the UK at the beginning of the summer months. However Dr Alba Rodriguez-Meira, 28, said that those sunny weeks were like an “extended lockdown”.
At the time, labs had been shut for nearly four months and Dr Rodriguez-Meira worked more than 90 hours a week – equivalent to 13 hours a day, 7 days a week – to catch up her leukaemia research at the University of Oxford.
“That was fine during the first month but it becomes a bit disruptive in terms of life quality if you try to do it for much longer,” Dr Rodriguez-Meira said.
Her weekly hours are slowly returning to her usual 60 a week – but she’s still feeling the pressure.
“I’ve lost a lot of productivity – sometimes I think I’ve not been as happy or as passionate as I used to be.
“Working under these circumstances has made me lose a bit of that. And I am sometimes so, so, absolutely tired.”
Social distancing rules mean that even though labs have reopened, not everyone can be there at the same time.
This is affecting the work of PhD student Laurien van de Weijer, 24, who is studying meningioma, a kind of tumour which makes up over a third of primary central nervous system tumours.
An important experiment she was running at her lab at the University of Plymouth over Easter weekend in April failed because she could not get in to provide nutrients to the tumour cells, which subsequently died. She is apprehensive about the 18 months she has left to finish her doctorate.
“I’ll be so overloaded… because I lost lots of time in the early stage, I really have to catch up, so I probably will do crazy hours.
“I really don’t look forward to being in the lab in the middle of the night.”
Laurien is also concerned that the longer she takes to get her research done, “the longer there won’t be any good drugs” for people with meningiomas.
The Institute of Cancer Research (ICR) says the COVID pandemic will add on an extra two years to the lag time between new treatments being discovered and cancer patients being able to use them.
“We don’t have the luxury of time – that’s the truth – to wait for two extra years,” says Amani Liaquat, 23, who has an aggressive cancerous brain tumour known as a glioblastoma multiforme, and according to doctors has between 12 and 18 months to live.
Amani is now trying a new drug called ONC201 which is still in trials, after chemotherapy and radiotherapy have both failed to shrink the tumour
Amani says she “can’t really put into words” how grateful she is to researchers going into labs during the pandemic, “risking their own health to try and help others”.
“The fact that people are still out there, trying their best in such difficult circumstances is really important,” she says.
Spurred on by stories like Amani’s, some groups of so-called “wet lab” researchers, whose work is experiment-heavy, have come up with shifts that allow them in to labs while observing social distancing.
It’s often after midnight when Beshara Sheehan begins her cycle home from the ICR lab in Sutton, south London.
Beshara Sheehan, 28, whose research is on improving prostate cancer therapy, works a lot of late shifts, often cycling home at midnight. She finds it “difficult to switch off” from work, having to still communicate with on-shift colleagues..
Fiona Want, 25, works at the same site as Beshara, albeit in a different research team, but prefers early morning shifts over late ones.
“It took a bit of getting used to having that real jumble of routine,” said Fiona, who has walked half her day at the lab and half at home.
Her research is on bladder cancer, and works up to 55 hours a week, 10 hours more than pre-COVID. She is driven on by the death of her fiance’s dad from cancer at the end of last year.
“That’s been a real source of motivation for me to keep working hard and a reminder that everyone’s life is, in some way, impacted by cancer,” she said.
“It is so important that we don’t let research slow down and keep pushing forward with discoveries that ultimately save lives.”
Scientists have taken a step closer to understanding how some rare people’s immune systems can suppress HIV.
The innate immune response mounts a fast-acting, general response against pathogens or supports the adaptive immune response, made up of antibodies and T cells that learn to fight specific pathogens after infection or vaccination
In recent years, researchers discovered that some components of the innate immune response can, under certain conditions, also be trained in response to infectious pathogens, such as HIV.
In a study recently published in the Journal of Clinical Investigation, it was shown that elite controllers, a rare subset of people whose immune system can control HIV without the use of drugs, have myeloid dendritic cells, part of the innate immune response, that display traits of a trained innate immune cell.
“Using RNA-sequencing technology, we were able to identify one long-noncoding RNA called MIR4435-2HG that was present at a higher level in elite controllers’ myeloid dendritic cells, which have enhanced immune and metabolic states,” explained Xu Yu, MD, a Core Member of the Ragon Institute of MGH, MIT and Harvard. “Our research shows that MIR4435-2HG might be an important driver of this enhanced state, indicating a trained response.”
Myeloid dendritic cells’ main role is the support of T cells, which are key to the elite controllers’ ability to control HIV infection. Since MIR4435-2HG was found to be higher only in the cells of elite controllers, Dr Yu explained, it may be part of a learned immune response to infection with HIV. Myeloid dendritic cells with elevated MIR4435-2HG also had greater levels of a protein known as RPTOR, which drives metabolism. Because of this boosted metabolism, the myeloid dendritic cells may better support the T cells controlling the HIV infection.
“We used a novel sequencing technology, called CUT&RUN, to study the DNA of these cells,” says postdoctoral fellow Ciputra Hartana, MD, Ph.D., the paper’s first author. “It allowed us to study epigenetic modifications like MIR4435-2HG, which are molecules that bind to the DNA and change how, or if, the DNA is read by the cell’s machinery.”
The team found that MIR4435-2HG’s mechanism could function by attaching to the DNA near the location of the RPTOR gene. The bound MIR4435-2HG would then prompt cellular machinery to synthesise more RPTOR protein, from the instructions in the RPTOR gene. This kind of epigenetic modification, a ‘trained’ response to HIV infection, would keep the myeloid dendritic cells in a state of heightened metabolism, providing long-term support to the T cells battling the virus.
“Myeloid dendritic cells are very rare immune cells, accounting for only 0.1-0.3% of cells found in human blood,” said Dr Yu. “We were fortunate and thankful to have access to hundreds of millions of blood cells from the many study participants who have donated their blood to support our HIV research. These donations were key to making this discovery.”
A core component of HIV cure research is to figure out exactly how elite controllers’ immune systems can keep HIV under control. By understanding how elite controllers keep the deadly virus in check, scientists could develop treatments to enable other people living with HIV to replicate the same immune response. This would take away the need for daily medication to control the virus, achieving what is known as a ‘functional cure’.
Journal information: Ciputra Adijaya Hartana et al, Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers, Journal of Clinical Investigation (2021). DOI: 10.1172/JCI146136
