In the open-access journal PLOS Biology, researchers present the first evidence of 12-hour cycles of gene activity in the human brain. Led by Madeline R. Scott, the study also reveals that some of those 12-hour rhythms are missing or altered in the postmortem brains of patients with schizophrenia.
Schizophrenia patients are known to have disturbances in several types of 24-hour bodily rhythms, including sleep/wake cycles, hormone levels, and gene activity in the prefrontal cortex of the brain. However, virtually nothing is known about gene activity in the brain for cycles that are shorter than the usual 24-hour circadian rhythm. A few years ago, researchers discovered that certain genes in the body were associated with 12-hour bodily rhythms, which may have an origin in the 12-hour cycle of ocean tides.
As it is not possible to measure gene transcript levels in living brains, the new study instead used a time-of-death analysis to search for 12-hour rhythms in gene activity within postmortem brains. They focused on the dorsolateral prefrontal cortex as it is associated with cognitive symptoms and other abnormalities in gene expression rhythms that have been observed in schizophrenia.
Numerous genes in the normal dorsolateral prefrontal cortex were found to have 12-hour rhythms in activity. Among them, gene activity levels related to building connections between neurons peaked in the afternoon/night, while those related to mitochondrial function (and therefore cellular energy supply) peaked in the morning/evening.
In contrast, postmortem brains from patients with schizophrenia contained fewer genes with 12-hour activity cycles, and those related to neural connections were missing entirely. Additionally, although the mitochondria-related genes did maintain a 12-hour rhythm, their activity did not peak at the normal times. Whether these abnormal rhythms underlie the behavioural abnormalities in schizophrenia, or whether they result from medications, nicotine use, or sleep disturbances should be examined in future studies.
Co-author Colleen A. McClung adds: “We find that the human brain has not only circadian (24 hour) rhythms in gene expression but also 12-hour rhythms in a number of genes that are important for cellular function and neuronal maintenance. Many of these gene expression rhythms are lost in people with schizophrenia, and there is a dramatic shift in the timing of rhythms in mitochondrial-related transcripts which could lead to suboptimal mitochondrial function at the times of day when cellular energy is needed the most.”
A new study suggests that some patients diagnosed with behavioural-variant frontotemporal dementia (bvFTD) – a presently incurable, mentally debilitating condition – may instead have a cerebrospinal fluid leak, which is detectable on MRI scans and often treatable. The researchers say these findings, published in the peer-reviewed journal Alzheimer’s & Dementia: Translational Research and Clinical Interventions, could lead to a cure.
“Many of these patients experience cognitive, behavioural and personality changes so severe that they are arrested or placed in nursing homes,” said Wouter Schievink, MD, professor of Neurosurgery at Cedars-Sinai. “If they have behavioural-variant frontotemporal dementia with an unknown cause, then no treatment is available. But our study shows that patients with cerebrospinal fluid leaks can be cured if we can find the source of the leak.”
When cerebrospinal fluid (CSF) leaks into the body, the brain can sag, causing dementia symptoms. Schievink said many patients with brain sagging, detectable in MRI, go undiagnosed, and he advises clinicians to take a second look at patients with telltale symptoms.
“A knowledgeable radiologist, neurosurgeon or neurologist should check the patient’s MRI again to make sure there is no evidence for brain sagging,” Schievink said.
Clinicians can also ask about a history of severe headaches that improve when the patient lies down, significant sleepiness even after adequate night-time sleep, and whether the patient has ever been diagnosed with a Chiari brain malformation, a condition in which brain tissue extends into the spinal canal. Brain sagging, Schievink said, is often mistaken for a Chiari malformation.
Even when brain sagging is detected, the source of a CSF leak can be difficult to locate. When the fluid leaks through a tear or cyst in the surrounding membrane, it is visible on CT myelogram imaging with the aid of contrast medium.
Schievink and his team recently discovered an additional cause of CSF leak: the CSF-venous fistula. In these cases, the fluid leaks into a vein, making it difficult to see on a routine CT myelogram. To detect these leaks, technicians must use a specialized CT scan and observe the contrast medium in motion as it flows through the cerebrospinal fluid.
In this study, investigators used this imaging technique on 21 patients with brain sagging and symptoms of bvFTD, and they discovered CSF-venous fistulas in nine of those patients. All nine patients had their fistulas surgically closed, and their brain sagging and accompanying symptoms were completely reversed.
“This is a rapidly evolving field of study, and advances in imaging technology have greatly improved our ability to detect sources of CSF leak, especially CSF-venous fistula,” said Keith L. Black, MD, chair of the department of Neurosurgery at Cedars-Sinai. “This specialised imaging is not widely available, and this study suggests the need for further research to improve detection and cure rates for patients.”
The remaining 12 study participants, whose leaks could not be identified, were treated with nontargeted therapies designed to relieve brain sagging, such as implantable systems for infusing the patient with CSF. However, only three of these patients experienced relief from their symptoms.
“Great efforts need to be made to improve the detection rate of CSF leak in these patients,” Schievink said. “We have developed nontargeted treatments for patients where no leak can be detected, but as our study shows, these treatments are much less effective than targeted, surgical correction of the leak.”
Cancer-associated fibroplasts surrounding a prostate tumour. Credit: Moscat and Diaz Meco labs
Prostate cancer is the second most common cancer and the second leading cause of cancer death among American men. Now, researchers have discovered key molecular players that drive prostate cancer to progress into a highly aggressive form of the disease called neuroendocrine prostate cancer that currently has no effective treatment. The finding, published in in the journal Scientific Reports, opens new avenues to therapeutics to treat neuroendocrine prostate cancer.
“We have found novel pathways that promote neuroendocrine prostate cancer,” says senior author Lucia R. Languino, PhD, a professor in the department of Pharmacology, Physiology and Cancer Biology and director of the Genetics, Genomics, and Cancer Biology PhD Program at Thomas Jefferson University.
Most prostate cancers are a type of disease called prostate adenocarcinoma. Other types of prostate cancer, including neuroendocrine tumours, are rare. However, unlike prostate adenocarcinoma, neuroendocrine prostate cancer is very aggressive and can quickly spread to other parts of the body. Treatments that are effective for adenocarcinomas in the prostate do not work against neuroendocrine prostate cancers.
Adenocarcinoma prostate cancers can progress into neuroendocrine prostate cancer. Until now, how this transition occurs has been a mystery.
To better understand how neuroendocrine prostate cancer develops, Dr Languino and colleagues looked for biomarkers of the disease. In previous work, they discovered that a molecule known as aVb3 integrin is abundant in mice and humans with neuroendocrine prostate cancer, but missing in prostate adenocarcinoma.
To look for molecules unique to neuroendocrine prostate cancer, the researchers found that aVb3 integrin expression in prostate cancer cells bumped up the expression of a known marker of neuroendocrine prostate cancer and significantly increased the expression of a molecule called Nogo receptor 2 (NgR2).
The finding “was a big discovery,” Dr Languino says. That’s because NgR2 is a protein found in nerve cells, where it contributes to neuronal functions. It has never before been studied in cancer, of any kind.
Dr Languino and her colleagues wanted to find out what this molecule, a neuronal protein, is doing in cancer.
An initial experiment revealed that NgR2 binds the aVb3 integrin. The scientists also saw that in mice with neuroendocrine prostate tumors, aVb3 integrin and NgR2 were both present in the primary tumor and in cancerous lesions that had formed in the lungs of the animals. A follow-up experiment made it clear that both aVb3 integrin and NgR2 are necessary for neuroendocrine prostate cancers.
When Dr Languino and her team lowered the amount of NgR2 in neuroendocrine prostate cancer cells, neuroendocrine markers also decreased. The results suggest that NgR2 plays a role in the development of neuroendocrine prostate cancer. Lowering the amount of NgR2 also reduced the ability of cancer cells to grow and move, indicating that NgR2 may have a hand in cancer spreading to other parts of the body, in a process known as metastasis. Metastases are often what makes cancers fatal.
“These two molecules, aVb3 integrin and NgR2, seem to create a combination that is lethal,” Dr Languino says.
She and her colleagues are now looking for a molecule or antibody that would block the effect of NgR2, or the aVb3 integrin/NgR2 complex, to inhibit their ability to promote neuroendocrine prostate cancer growth and development, and make the cancer more susceptible to therapy.
The chemical DEET has proven effective at keeping disease-carrying mosquitoes at bay, but the repellent is smelly and its protection is short-lived. Now, researchers report in the Journal of Agricultural and Food Chemistry that they have designed safe alternatives with some advantages over DEET, including a nice smell and much longer protection.
DEET disrupts a mosquito’s ability to locate humans. Until recently, it was considered the gold standard among topical repellents, but some find its strong odor offensive. It has to be reapplied frequently, and at high concentrations, it can damage synthetic fabrics and plastics. Another popular repellent known as picaridin is now regarded as a better alternative, since its protective effect lasts longer, and it doesn’t have an odor or damage items. However, like DEET, it has to be reapplied after swimming or sweating.
So, Francesca Dani and colleagues wanted to look for alternatives to these established products. In prior work, the team used as starting materials two plant-based natural repellents that offered only short-term protection from mosquitoes. The researchers converted these terpenoids into cyclic acetals and hydroxyacetals, thereby extending their protective timespan beyond that of DEET. But the researchers wanted to improve on these initial products.
In the current work, the team synthesised additional cyclic hydroxyacetals from inexpensive, commercially available carbonyls. The new cyclic compounds had pleasant, much fainter odors and were easier to dissolve in water, meaning they can be formulated without high concentrations of alcohol. Some were as effective as DEET and picaridin at repelling Asian tiger mosquitoes, which have spread widely in the U.S. and carry diseases, including encephalitis, dengue and dog heartworm. And like picaridin, they provided human volunteers more than 95% protection from bites for at least eight hours, while DEET’s protection rapidly declined below that level after just two hours.
Toxicity of some of the most active new compounds was comparable to or lower than the traditional repellents. Two hydroxyacetals were also less likely to cause immune reactions or to penetrate cell layers than picaridin. The researchers conclude that their compounds represent a new class of promising mosquito repellents that can compete favorably with DEET and picaridin in terms of efficacy and safety.
While chemotherapy is highly effective at killing cancer cells, it also kills healthy cells, something which medical research is trying minimise. Recently, ‘chronochemotherapy’ has garnered growing attention in the research community. As the name suggests, the aim is timing the delivery of the drug when the body is least vulnerable to the harmful effects of the drug, while the cancer cells are at their most vulnerable.
Chronochemotherapy exploits the fact that human physiological processes, including cell proliferation and differentiation, are regulated by the circadian clock. However, it is not yet widely exploited in real-world clinical settings because there at present is no systematic method to find the optimal chemotherapy delivery time.
This problem was tackled by an interdisciplinary team of researchers from the Institute for Basic Science (IBS), South Korea. They were led by the principal investigators, mathematician Kim Jae Kyoung at IBS and oncologist Koh Youngil at Seoul National University Hospital. The researchers studied a group of patients suffering from diffuse large B-cell lymphoma (DLBCL), which accounts for about 30 to 40% of non-Hodgkin’s lymphoma. Their findings are published in the journal JCI Insights.
The research team noticed that DLBCL patients at Seoul National University Hospital received chemotherapy at two different schedules, with some patients receiving morning treatment (8:30), while others taking the drugs in the afternoon (14:30). All patients received R-CHOP, which is a combination of targeted therapy and chemotherapy, 4 to 6 times in the morning or afternoon at intervals of about 3 weeks.
Figure 1. Chemotherapy in the afternoon can improve treatment outcomes The daily fluctuation of proliferative activity of bone marrow is larger in females than in males, and it becomes higher in the morning (left). Thus, chemotherapy in the morning strongly inhibits proliferative activity in female lymphoma patients, resulting in a higher incidence of adverse events such as neutropenia and infections. This forces the clinicians to reduce the dose intensity (center). Consequently, female patients undergoing the morning treatment show a lower survival probability than those undergoing the afternoon treatment (right). Specifically, only ~13% of female patients treated in the afternoon had a worse outcome and ~2% of them died while ~37% of female patients treated in the morning had a worse outcome and ~25% of them died. Male patients did not show any difference in treatment outcomes depending on the chemotherapy delivery time.
They analysed 210 patients to investigate differences between morning and afternoon treatment. They found that female patients who received afternoon treatment had 12.5 times reduced mortality rate (25% to 2%), while the cancer recurrence after 60 months was decreased by 2.8 times (37% to 13%). In addition, chemotherapy side effects such as neutropenia were more common in female patients who received morning treatment.
Surprisingly, there was no difference in treatment efficiency depending on the treatment schedule in the case of male patients.
To understand the cause of gender differences, the research team analysed ~14 000 blood samples from the Seoul National University Hospital Health Examination Center. It was found that in females, white blood cell count tends to decrease in the morning and increase in the afternoon. This indicates that the bone marrow proliferation rate is higher in the morning than in the afternoon because there is a ~12hr delay between the bone marrow proliferation and blood cell production.
This means that if a female patient receives chemotherapy in the morning when bone marrow is actively producing blood cells, the possibility of adverse side effects becomes greater. These results are consistent with the findings from recent randomised clinical trials that showed female colorectal cancer patients treated with irinotecan in the morning suffered from higher drug toxicities.
One confounding variable was the drug dose. Since the morning female patients suffered from greater adverse side effects, oftentimes the dose had to be reduced in these patients. On average, the drug dose was reduced by ~10% compared to the dose intensity given to female patients receiving the afternoon treatment.
Unlike female patients, it was found that male patients did not show a significant difference in white blood cell count and bone marrow cell proliferation activity throughout the day, which is the reason why the timing of the treatment had no impact.
Professor Koh Young-il said, “We plan to verify the conclusions of this study again with a large-scale follow-up study that completely controls confounding variables, and to confirm whether chemotherapy has similar effects in other cancers.”
Ci Kim Jae Kyung said, “Because the time of the internal circadian clock can vary greatly depending on the individual’s sleep-wake patterns, we are currently developing a technology to estimate the time of the circadian clock from the patient’s sleep pattern. We hope that it can be used to develop an individualised anti-cancer chronotherapy.”
Haemostatic microneedle technology can be applied like a typical adhesive bandage to quickly stop bleeding. The biocompatible and biodegradable microneedle arrays (MNAs) on the patch increase its surface contact with blood to accelerate the clotting process and also increase the adhesive properties of the patch via mechanical interlocking to promote wound closure. Credit: Designed by Amir Sheikhi and Reihaneh Haghniaz/Executed by Natan Barros. All Rights Reserved.
In the US, secondary, uncontrolled bleeding from traumatic injury is the leading cause of death from ages one to 46. Amir Sheikhi, assistant professor of chemical engineering and of biomedical engineering at Penn State, has a plan to change that with a novel microneedle patch that can immediately stop bleeding after injury.
He described his technology in a new paper in the journal Bioactive Materials.
“Excessive bleeding is a serious challenge for human health,” Sheikhi said. “With haemorrhaging injuries, it is often the loss of blood – not the injury itself – that causes death. There is an unmet medical need for ready-to-use biomaterials that promote rapid blood coagulation.”
Sheikhi’s haemostatic microneedle technology can be applied like a typical adhesive bandage to quickly stop bleeding. The biocompatible and biodegradable microneedle arrays (MNAs) on the patch increase its surface contact with blood, accelerating the clotting process. The needles also increase the adhesive properties of the patch via mechanical interlocking to promote wound closure.
“In vitro, the engineered MNAs reduced clotting time from 11.5 minutes to 1.3 minutes; and in a rat liver bleeding model, they reduced bleeding by more than 90%,” Sheikhi said. “Those 10 minutes could be the difference between life and death.”
The MNA patch is comparable hydrogel technology that is currently used to treat bleeding wounds in hospitals, but hydrogel applications require preparation and medical expertise. The microneedle patch is pre-engineered for immediate application that anyone can use to stop bleeding, Sheikhi said, much like a typical over-the-counter adhesive bandage.
Microneedles – which are already in use to deliver biologics, such as cells or drugs, through the skin or for cosmetic procedures to stimulate collagen production – are tiny, making their application pain-free, according to Sheikhi.
The researchers are now working to commercialise the patch, with more testing plans.
In October last year, the National Institute for Communicable Diseases (NICD) alerted the public to a measles outbreak in Limpopo. Since then, four more provinces have reported outbreaks, and the number of positive cases in the country has climbed rapidly.
Last week’s measles report from the NICD indicated that between the first week of October 2022 and mid-week in the second week of January 2023, a total of 397 cases of measles were identified across the country. Of those, 382 cases were detected in five provinces – Limpopo 145, North West 125, Mpumalanga 79, Gauteng 18, and the Free State 15. These five provinces have all met the criteria for a measles outbreak (three or more cases in a district within a month).
The remaining 15 cases are spread around KwaZulu-Natal, Northern Cape, the Eastern Cape, and the Western Cape – none of which have so far met the criteria for an outbreak.
‘Biggest outbreak in 11 years’
Dr Kerrigan McCarthy, a pathologist from the Centre for Vaccines and Immunology at the NICD, tells Spotlight that this is the biggest outbreak in 11 years, surpassing the outbreak in 2017 when around 280 cases of measles were identified.
According to the NICD report, the total number of laboratory-confirmed measles cases and the total number of samples submitted for testing has decreased for the third consecutive week. However, McCarthy cautions that this apparent decline might actually be due to a decrease in the number of specimens sent to the NICD for testing, and not to the outbreak actually slowing down.
“The fact that we have seen a decrease in the number of positive cases could be attributed to the decrease in number of specimens that have been submitted, but there is a small possibility that it could represent a turnaround in the outbreak. However, a consensus amongst us in public health is that it is the former problem,” says McCarthy.
She adds that the true extent of this outbreak – and whether new cases have really declined or not – may only become clear in the next few weeks, as schools across the country resume activities.
While it isn’t possible to predict exactly where the outbreak is going, McCarthy says at the moment it is following a similar trend to the widespread measles outbreak that occurred just over a decade ago. “In 2009 to 2011 we had an outbreak of over 22 000 measles cases… and in fact, in that outbreak, we saw a similar pattern. The outbreak was declared in late 2009 and cases started increasing into December and then when the schools closed and December holidays happened, there was a lull in cases and then when the schools returned there was a massive increase in cases,” she says.
Fears of much larger outbreaks
In a Spotlight article published in July last year, Dr Haroon Saloojee, Professor and Head of the Division of Community Paediatrics at the University of the Witwatersrand, and other experts warned that low vaccination rates may lead to measles outbreaks of the type we are now seeing. Now they are concerned that things might get worse.
Saloojee agrees that it isn’t possible to predict exactly how this outbreak will behave. “There are obviously three possible outcomes,” he says, “An increase, levelling off, or decline. My fear and expectation [are] that the outbreak will continue to expand. There are more than a million unvaccinated children under five, and possibly about 2.5 million unvaccinated under 15 years.
“We should be greatly concerned. It is highly likely that the outbreak will extend beyond the five provinces and affect all provinces in the country,” he says.
He adds that children are protected from measles through vaccination and if 95% of children are vaccinated against measles, then this herd immunity will protect the 5% who are not vaccinated. But in South Africa, measles coverage is not at 95%.
“In South Africa, at best, about 80% of children are vaccinated [against measles]. The proportion is lower in some provinces. Thus, all children, but particularly unvaccinated children, are at risk of acquiring measles,” he says. “We haven’t had a serious problem [with] measles in South Africa for at least the last 20 years. But in other low- and middle-income countries, it is still one of the five major causes of child mortality.”
Mass measles immunisation campaign needed
Saloojee tells Spotlight the only way to curtail the outbreak at this point is through a national supplementary mass measles immunisation campaign.
“There is only one option at this stage, as we are facing a crisis. A national supplementary immunisation campaign is warranted, despite its high cost and resource demands,” he says. “Such activities have already commenced in the affected provinces and will be extended to other provinces if the outbreak continues to spread. The aim of the campaign is to boost measles vaccine coverage to the 95% mark in the short term, so that herd immunity can kick in.”
How did we get here?
While such an immunisation campaign should help mitigate the current spread of measles, the question remains how a widespread outbreak could occur in the first place given South Africa’s well-established childhood immunisation programme.
“The outbreak was entirely predictable and preventable,” says Saloojee. “We have had similar outbreaks [about] every five years since 2000. Paradoxically, COVID delayed this outbreak, which should have happened in 2020 because the isolation measures protected against measles spread too.”
“However, we cannot run away from the fact that too few children receive all their routine vaccinations, and there is little being done to systematically change this such as stopping vaccine stockouts, and clinics and hospitals reducing missed opportunities to vaccinate eligible children,” he says. “If nothing is done, we can count on another outbreak in 2028.”
Countries across the world are reporting measles outbreaks, according to the CDC, which is being attributed to a disruption in services like routine immunisation because of the COVID pandemic. However, according to Saloojee, South Africa’s outbreak cannot be attributed exclusively to the pandemic disrupting services, instead, it is also due to years of suboptimal measles vaccine coverage.
Spotlight previously reported in-depth on results from the 2019 Expanded Programme on Immunisation (EPI) National Coverage survey, which showed that only around 77% (76.8%) of the children surveyed had received all fourteen age-appropriate vaccines from birth to 18 months. This includes the two doses of the measles vaccine.
Dr Lesley Bamford, a child health specialist in youth and school health at the National Department of Health, provided Spotlight with a table showing measles vaccination coverage per province between 2017 and 2022.
Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health
According to the figures provided by Bamford, national coverage for the first dose of the measles vaccine has improved from 80% in 2017-2018 to 88% in 2021-2022. However, coverage for the second measles dose remained stuck in a narrow band from 77% to 80%, until 2021-2022, when it improved to 84% – still well below the 95% coverage required for herd immunity.
Expanded vaccination campaign
The NICD report shows the highest number of measles cases so far have been in the five to nine-year age group, which represents 40% of cases. 29% of cases were in the one to four age group and 17% in the 10 to 14-year age group. The remaining cases occurred in children younger than one year and those aged 15 and older.
According to McCarthy, based on the distribution of cases in these age groups, the NICD recommended to the National Department of Health that it extend its planned mass measles vaccination campaign to include children between six months and 15 years of age – which the Department has agreed to do.
Bamford tells Spotlight that a mass measles immunisation campaign had already been planned across all provinces for February 2023. But for the five provinces experiencing outbreaks, the timeline has since moved up. The four remaining provinces will still start their campaigns in February as planned.
“The target age group for that campaign has been extended. So, the initial plan was targeting children under 5 years of age and now in most provinces, it has been extended to include all children six months to 15 years of age,” she says.
Spokesperson for the National Department of Health, Foster Mohale confirms that all children between the ages of six months and 15 years, regardless of documentation, are eligible to receive their measles vaccination in the catch-up drive. “Most provinces have been vaccinating all children between 6 months and 15 years, with [or] without documents because diseases have no discrimination. So, we haven’t received any concern or report about non-vaccination of children without documentation,” he says.
Bamford adds that a measles incident management team has been established by the National Department of Health, which meets with the NICD and the provinces on a weekly basis.
She says Limpopo started its campaign in November, Mpumalanga and North West started in December, and Gauteng and the Free State started in January. The campaigns have so far been conducted mainly at primary healthcare clinics and outreach to ECD centres but now that the school year has resumed, children will also be vaccinated at schools.
Because the provinces all started at different times, there is no specific timeline for the vaccination campaign to be completed, according to Bamford, but the expectation from the National Department is that all provinces will wrap up their campaigns by mid-February when the HPV vaccination campaign kicks off.
“We know that measles coverage is suboptimal, and that is why we were planning to run a campaign, but of course, that is the single biggest reason why we are now experiencing these outbreaks,” she says. “The only way really to stop measles outbreaks is to improve immunisation coverage.”
In recent times, new drug discoveries by independent large pharmaceutical companies have become increasingly rare, with almost 60% of new drugs discovered through mergers and acquisitions and drug licensing. Fortunately, an emerging trend of spinouts from academia and R&D investments heralds a promising shift in the industry’s interorganisational deal networks to improve research and development in the future. Researchers explore this new trend in Drug Discovery Today.
Launching a new drug in the market is risky, thanks to a low probability of success during the research and development (R&D) phase and the high costs involved. But through an improved understanding of disease biology, decision-making can be more streamlined through the effective use of scientific information.
With this in mind, researchers from Ritsumeikan University, Japan, led by Associate Professor Kota Kodama are uncovering how the trends in interorganisational deals in the pharmaceutical industry are changing to improve R&D productivity and drug discovery. “The network structure of innovation creation in the pharmaceutical industry has changed with the increasing emergence of start-up companies spinning out from academia and research institutions as players in the source of innovation,” explains Dr Kodama.
Their research suggests that the knowledge necessary for breakthrough innovation in drug discovery is more often than not obtained through alliance networks. Over the past decade, large research-based pharmaceutical companies have used research collaborations, innovation incubators, academic centres of excellence, public-private partnerships, mergers and acquisitions (M&As), drug licensing, and corporate venture capital funds as typical methods for external innovation. The researchers now aim to define the changes in the network structure and nature of such alliances that have occurred over the past decade to provide future strategic insights for industry and academic players involved in drug discovery.
Using data from the Cortellis Competitive Intelligence database, the researchers identified nearly 50 000 deals of various kinds related to pharmaceutical R&D across pharmaceutical, digital health software, animal drug, and medical device companies to uncover trends in the creation of new drugs for human use. They also studied the trends of 13 of the largest pharmaceutical companies with annual revenues of more than US$10 billion, who saw an improvement in their CAGR (compound annual growth rate) since 2015. The researchers noticed that the rising CAGR correlated to a significant change in M&A-related deals after 2015, indicating that M&A-related deals drive revenue growth for large pharmaceutical companies.
Furthermore, the number of organisations involved in interorganisational deals has been increasing yearly from 2012 to 2021. Although the number of organisations involved and the number of deals may be increasing, the density of the deal networks is decreasing annually, suggesting that networks are becoming more non-cohesive. The concentration of business relationships between organisations of certain areas in the network changed to dispersion around 2015, and new networks connecting different groups started to form after 2017. These trends are an important illustration of how the industry landscape is gradually evolving away from the traditional network in which large pharmaceutical companies drove drug discovery output. Now, interorganisational deals among more diverse players have become active and are driving R&D productivity for startups in biotechnology and pharmaceuticals.
A clear increase in the number of academia-owned spinouts of advanced technology and expansion of investment in start-ups is a positive sign. The emergence of new chemical modalities, such as biologics, oligonucleotides, and peptides that differ from traditional small molecule drug discovery indicate remarkable changes that have taken place over the past two decades. The trend of increased financing for start-up companies in personalised drug development is beneficial for patent creation and will positively impact innovation creation in the coming years.
“The presence of academia to support the technologies of these start-ups is becoming very important, and government and private support and investment in this area is boosting innovation. Our study shows that such medium- and long-term support may ultimately benefit the health and well-being of humankind,” concludes an optimistic Dr Kodama.
Recreational running offers a lot of physical and mental health benefits – but some people can develop exercise dependence, a form of addiction to physical activity which can cause health issues. Shockingly, signs of exercise dependence are common even in recreational runners. A study published in Frontiers in Psychology investigated whether the concept of escapism can help us understand the relationship between running, well-being, and exercise dependence.
“Escapism is an everyday phenomenon among humans, but little is known regarding its motivational underpinnings, how it affects experiences, and the psychological outcomes from it,” said Dr Frode Stenseng of the Norwegian University of Science and Technology, lead author of the paper.
Running to explore or to evade?
“Escapism is often defined as ‘an activity, a form of entertainment, etc. that helps you avoid or forget unpleasant or boring things.” In other words, many of our everyday activities may be interpreted as escapism,” said Stenseng. “The psychological reward from escapism is reduced self-awareness, less rumination, and a relief from one’s most pressing, or stressing, thoughts and emotions.”
Escapism can restore perspective, or it can act as a distraction from problems that need to be tackled. Escapism which is adaptive, seeking out positive experiences, is referred to as self-expansion. Meanwhile maladaptive escapism, avoiding negative experiences, is called self-suppression. Effectively, running as exploration or as evasion.
“These two forms of escapism are stemming from two different mindsets, to promote a positive mood, or prevent a negative mood,” said Stenseng.
Escapist activities used for self-expansion have more positive effects but also more long-term benefits. Self-suppression, by contrast, tends to suppress positive feelings as well as negative ones and lead to avoidance.
Self-suppression associated with exercise dependence
The team recruited 227 recreational runners, half men and half women, with widely varying running practices. They were asked to fill out questionnaires which investigated three different aspects of escapism and exercise dependence: an escapism scale which measured preference for self-expansion or self-suppression, an exercise dependence scale, and a satisfaction with life scale designed to measure the participants’ subjective well-being.
The scientists found that there was very little overlap between runners who favoured self-expansion and runners who preferred self-suppression modes of escapism. Self-expansion was positively related with well-being, while self-suppression was negatively related to well-being. Self-suppression and self-expansion were both linked to exercise dependence, but self-suppression was much more strongly linked to it. Neither escapism mode was linked to age, gender, or amount of time a person spent running, but both affected the relationship between well-being and exercise dependence. Whether or not a person fulfilled criteria for exercise dependence, a preference for self-expansion would still be linked to a more positive sense of their own well-being.
Although exercise dependence corrodes the potential well-being gains from exercise, it seems that perceiving lower well-being may be both a cause and an outcome of exercise dependency: the dependency might be driven by lower well-being as well as promoting it.
Similarly, experiencing positive self-expansion might be a psychological motive that promotes exercise dependence.
“More studies using longitudinal research designs are necessary to unravel more of the motivational dynamics and outcomes in escapism,” said Stenseng. “But these findings may enlighten people in understanding their own motivation, and be used for therapeutic reasons for individuals striving with a maladaptive engagement in their activity.”
Sleep deprivation is bad for memorisation, something which still doesn’t deter many med students from late night cramming. Researchers however have discovered that memories learned during sleep deprivation is not necessarily lost, it is just difficult to recall. Publishing in the journal Current Biology, the researchers have found a way to make this ‘hidden knowledge’ accessible again days after studying whilst sleep-deprived using optogenetic approaches and the asthma drug roflumilast.
University of Groningen neuroscientist Robbert Havekes and his team have extensively studied how sleep deprivation affects memory processes. “We previously focused on finding ways to support memory processes during a sleep deprivation episode,” says Havekes. However, in his latest study, his team examined whether amnesia as a result of sleep deprivation was a direct result of information loss, or merely caused by difficulties retrieving information. “Sleep deprivation undermines memory processes, but every student knows that an answer that eluded them during the exam might pop up hours afterwards. In that case, the information was, in fact, stored in the brain, but just difficult to retrieve.”
Priming the hippocampus
To find out, the researchers selectively introduced optogenetic proteins into neurons that are activated during a learning experience, enabling recall of a specific experience by shining a light on the cells. “In our sleep deprivation studies, we applied this approach to neurons in the hippocampus, the area in the brain where spatial information and factual knowledge are stored,” says Havekes.
First, the genetically engineered mice were given a spatial learning task in which they had to learn the location of individual objects, a process heavily reliant on neurons in the hippocampus. The mice then had to perform this same task days later, but this time with one object moved to a new location. The mice that were deprived of sleep for a few hours before the first session failed to detect this spatial change, which suggests that they cannot recall the original object locations. “However, when we reintroduced them to the task after reactivating the hippocampal neurons that initially stored this information with light, they did successfully remember the original locations,” says Havekes. “This shows that the information was stored in the hippocampus during sleep deprivation, but couldn’t be retrieved without the stimulation.”
Memory problems
The molecular pathway set off during the reactivation is also targeted by the drug roflumilast, which is used by patients with asthma or COPD. Havekes says: “When we gave mice that were trained while being sleep deprived roflumilast just before the second test, they remembered, exactly as happened with the direct stimulation of the neurons.” Since roflumilast is approved for use in humans and can enter the brain, this may lead to testing to see if it can recover ‘lost’ memories for humans..
It might be possible to stimulate the memory accessibility in people with age-induced memory problems or early-stage Alzheimer’s disease with roflumilast,” says Havekes. “And maybe we could reactivate specific memories to make them permanently retrievable again, as we successfully did in mice.” If a subject’s neurons are stimulated with the drug while they try and ‘relive’ a memory, or revise information for an exam, this information might be reconsolidated more firmly in the brain. “For now, this is all speculation of course, but time will tell.”
Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health
