Day: June 28, 2021

Categories : Regenerative MedicineTags :

Chemical Fingerprints Improve Stem Cell Production

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Photo by Louis Reed on Unsplash

Researchers in Japan have developed a new, noninvasive way to monitor the tricky art of stem cell production.

The current era of ethical stem cell research was ushered in by the 2012 Nobel prize-winning discovery that ordinary cells could be coaxed to revert to their earliest pluripotent stage ushered in. Suddenly, scientists could have an ethical, near-inexhaustible supply of pluripotent stem cells — the most versatile of stem cells — that can become any type of cell much like how embryonic stem cells function.

These reprogrammed cells called induced pluripotent stem cells (or iPS cells) hold great promise for regenerative medicine, where they can be used to develop tissue or organ replacement-based treatments for life-threatening diseases.

One key challenge is that it is a lengthy and delicate process to artificially induce ordinary cells to reset back to pluripotency. Obtaining iPS cells therefore is a matter of chance. However, knowing all they can about the complex chemical changes happening inside during reprogramming can help scientists increase the chances of successfully obtaining viable iPS cells for clinical applications. Current methods that track reprogramming status, however, use destructive and costly techniques.

A study led by Dr Tomonobu Watanabe, professor at Hiroshima University’s Research Institute for Radiation Biology and Medicine, showed that Raman spectroscopy could be a low-cost, simpler, and non-intrusive technique to monitor the cell’s internal environment as it transitions.

Dr Watanabe explained: “The quality evaluation and sorting of existing cells have been carried out by investigating the presence or absence of expression of surface marker genes. However, since this method requires a fluorescent antibody, it is expensive and causes a problem of bringing the antibody into the cells.”

He added that the “solution of these problems can accelerate the spread of safe and low-cost regenerative medicine using artificial tissues. Through our method, we provide a technique for evaluating and sorting the quality of iPS cells inexpensively and safely, based on scattering spectroscopy.”

Raman spectroscopy is an alternative to invasive approaches that require dyes or labels to extract biochemical information. It instead makes use of vibration signatures produced when light beams interact with chemical bonds in the cell. Since each chemical has its own distinct vibration frequency, scientists can use it to identify the cell’s molecular makeup.

The team used this spectroscopic technique to get the “chemical fingerprints” of mouse embryonic stem cells, the neuronal cells they specialised into, and the iPS cells formed from those neuronal cells. These data were then used to train an AI model to can track the reprogramming is progressing, and verify iPS cell quality by checking for a “fingerprint” match with the embryonic stem cell.

To measure the progress, they assigned the “chemical fingerprint” of neuronal cells as the transformation starting point and the embryonic stem cell’s patterns as the desired end goal. Along the axis, they used “fingerprint” samples collected on days 5, 10, and 20 of the neuronal cells’ reprogramming as reference points on how the process is advancing.

“The Raman scattering spectrum contains comprehensive information on molecular vibrations, and the amount of information may be sufficient to define cells. If so, unlike gene profiling, it allows for a more expressive definition of cell function,” Dr Watanabe said.

“We aim to study stem cells from a different perspective than traditional life sciences.”

Source: Hiroshima University

Journal information: Germond, A., et al. (2020) Following Embryonic Stem Cells, Their Differentiated Progeny, and Cell-State Changes During iPS Reprogramming by Raman Spectroscopy. Analytical Chemistry doi.org/10.1021/acs.analchem.0c01800.

Categories : Hospitals Obstetrics & GynaecologyTags :

Breakthrough AI Development for Premature Baby Care

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Photo by Hush Naidoo on Unsplash

Researchers believe they have made a breakthrough in the science of keeping premature babies alive.

As part of her PhD work, James Cook University engineering lecturer Stephanie Baker led a pilot study that used a hybrid neural network to accurately predict how much risk individual premature babies face. This study was published in the journal Computers in Biology and Medicine.

Complications resulting from premature birth are the leading cause of death in children under five and over 50% of neonatal deaths occur in preterm infants, she said. In 2005, 12.9 million births, or 9.6% of all births worldwide, were preterm.

“Preterm birth rates are increasing almost everywhere. In neonatal intensive care units, assessment of mortality risk assists in making difficult decisions regarding which treatments should be used and if and when treatments are working effectively,” said Ms Baker.

To better guide their care, preterm babies are often given a score that indicates the risk they face.

“But there are several limitations of this system. Generating the score requires complex manual measurements, extensive laboratory results, and the listing of maternal characteristics and existing conditions,” noted Ms Baker.

She said the alternative was to measure variables that do not change (eg, birthweight) that prevents recalculation of the infant’s risk on an ongoing basis and does not show their response to treatment.

“An ideal scheme would be one that uses fundamental demographics and routinely measured vital signs to provide continuous assessment. This would allow for assessment of changing risk without placing unreasonable additional burden on healthcare staff,” said Ms Baker.

She said the JCU team’s research had culminated in the Neonatal Artificial Intelligence Mortality Score (NAIMS), a hybrid neural network that relies on simple demographics and trends in heart and respiratory rate to determine mortality risk.

“Using data generated over a 12 hour period, NAIMS showed strong performance in predicting an infant’s risk of mortality within 3, 7, or 14 days.

“This is the first work we’re aware of that uses only easy-to-record demographics and respiratory rate and heart rate data to produce an accurate prediction of immediate mortality risk,” said Ms Baker.

According to Ms Baker, the technique was fast with no invasive procedures or knowledge of medical histories needed.

“Due to the simplicity and high performance of our proposed scheme, NAIMS could easily be continuously and automatically recalculated, enabling analysis of a baby’s responsiveness to treatment and other health trends,” said Ms Baker.

She said NAIMS had proved accurate when tested against hospital mortality records of preterm babies and had the added advantage over existing schemes of being able to perform a risk assessment based on any 12 hour period of data gathered during the patient’s stay.

Ms Baker said the next step in the process was partnering with local hospitals to gather more data and undertake further testing.

“Additionally, we aim to conduct research into the prediction of other outcomes in neo-natal intensive care, such as the onset of sepsis and patient length of stay,” said Ms Baker.

Source: James Cook University

Journal information: Baker, S., et al. (2021) Hybridized neural networks for non-invasive and continuous mortality risk assessment in neonates. Computers in Biology and Medicine. doi.org/10.1016/j.compbiomed.2021.104521.

Categories : COVIDTags :

Lockdown Level 4; Third Wave Driven by Delta Variant

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In response to the third wave driven by the delta variant, President Cyril Ramaphosa instituted a two-week Level 4 lockdown during a ‘family meeting’ address to the nation.

He warned that the healthcare system was facing a dire situation. “Our health facilities are stretched to the limit… ICU beds are in short supply,” he said. 

In a press briefing on Friday, the head of the World Health Organization said the COVID Delta variant, first seen in India, is “the most transmissible of the variants identified so far,” and warned it is now spreading in at least 85 countries.

“We are in the exponential phase of the pandemic with the numbers just growing very, very, extremely fast and (they) will keep growing in the next weeks,” said Tulio de Oliveira, a leading virologist in the country.

The Delta variant first seen in India now appears to be “dominating infections in South Africa,” de Oliveira of the Network for Genomic Surveillance in South Africa told a virtual briefing.

The Delta variant has emerged as dominant in South Africa. Source: Department of Science & Technology

Koleka Mlisana, the head of a government ministerial advisory committee on COVID, told the same briefing that there is “evidence that the Delta variant may actually be taking over”.

Acting Minister of Health, Mmamoloko Kubayi-Ngubane said that due to the prevalence of the Delta variant, infection numbers “are likely to surpass the second wave peak” in January.

Only about 2.4 million people have been immunised since February. Thousands of EFF activists rallied in Pretoria on Friday to demand a faster coronavirus vaccination rollout, including expedited approvals for the Sinovac vaccine from China and Russia’s Sputnik V.

Source: Medical Xpress

Categories : COVIDTags :

Preliminary Study Explains Why Delta Variant is So Infectious

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Colorized scanning electron micrograph of an apoptotic cell (purple) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

A preliminary study has possibly determined why the SARS-CoV-2 Delta variant is more infectious and pathogenic than its ancestor.

Through a series of in vitro experiments, researchers have discovered that variant’s enhanced ability to induce cell-to-cell fusion (syncytia) and reduced susceptibility to vaccine and infection-induced antibodies together help make the Delta variant more infectious than previously circulating variants. The study, which is yet to be peer reviewed, is currently available on the bioRxiv preprint server.

The SARS-CoV-2 virus has undergone more than 12 000 mutations since it was first detected in December 2019, most of which are neutral and do not contribute to viral evolution. However, the acquisition of specific mutations in structural and non-structural proteins has caused the emergence of novel, more virulent SARS-CoV-2 variants.

Spike protein mutations are particularly concerning as they can significantly influence viral infectivity, virulence, and immune evasion ability.

The B.1.617 lineage drove a massive surge in new COVID cases in India. This lineage is further divided into three sub-lineages, namely B.1.617.1, B.1.617.2, and B.1.617.3. Although these emerged first in India, the B.1.617.2 or Delta variant or soon became dominant in many countries, including South Africa where it has driven a new surge of infections, particularly in Gauteng Province. The World Health Organization (WHO) has designated the Delta variant as a ‘Variant of Concern’ (VOC) due to its significantly increased infectivity and pathogenicity.

In the current study, the scientists have evaluated the susceptibility of the Delta variant to neutralisation by vaccine or natural infection-induced antibodies.

Delta variant mutations 

The Delta variant’s spike protein contains nine mutations in the S1 subunit and one mutation in the S2 subunit. In the S1 subunit, five mutations are present in the N-terminal domain containing binding sites (epitopes) for neutralising antibodies. In addition, two mutations are present in the receptor-binding domain of the S1 subunit, which is known to influence antibody-mediated neutralisation and infectivity. Among the three remaining mutations, two are known to increase angiotensin-converting enzyme 2 (ACE2) binding, viral replication, and spike protein cleavage at the S1/S2 site.    

Delta variant host cell entry

Using African green monkey and human cells, the researchers found that Delta can enter kidney cells of both species with similar efficacy as the wild-type SARS-CoV-2. However, for human colon and lung cells, Delta showed 1.5-fold and 2-fold higher invading ability, respectively, compared to the wild-type virus. Since the Delta variant spike protein did not exhibit increased ACE2 binding, the scientists suggest that increased entry of B.1.617.2 into colon and lung cells is not mediated by enhanced ACE2 binding.

Besides inducing fusion between the viral envelope and host cell membrane, the spike protein triggers the fusion of infected cells with nearby cells to form large multinucleated cells, known as syncytia. Given the fact that spike-induced syncytia formation contributes to COVID pathogenesis, the scientists investigated whether Delta variant infection is associated with increased syncytia formation.

By conducting in vitro experiments on human lung cells expressing high levels of ACE2, they found that Delta spike expression leads to 2.5-fold higher and larger syncytia formation than the wild-type spike expression.

Delta variant’s immune evasion ability less than Beta?

The scientists tested the ability of four therapeutic monoclonal antibodies to neutralise the Delta variant, of which only Bamlanivimab failed. The other three antibodies exhibited similar efficacy in neutralising both wild-type virus and Delta variant.

Antibodies derived from COVID recovered patients, and BNT162b2-vaccinated individuals showed only slightly reduced efficacy in neutralising the Delta variant as compared to the wild-type virus. In contrast, the B.1.315 or Beta variant, first detected in South Africa, showed a significantly higher ability to evade infection- and vaccination-induced immunity.

In summary

The study showed that Delta’s increased ability to invade lung cells may enhance infectivity and pathogenicity. Though it has lower susceptibility to antibody-mediated neutralisation, it is possible that Delta may be effectively controlled by immunity developed in response to natural infection or vaccination.

Source: News-Medical.Net

Journal information: Arora P. 2021. Increased lung cell entry of B.1.617.2 and evasion of antibodies induced by infection and BNT162b2 vaccination. bioRxiv. https://www.biorxiv.org/content/10.1101/2021.06.23.449568v1

Categories : Substance UseTags :

Performance Enhancers Linked to Criminality

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Photo by Jonathan Borba on Unsplash

A new study shows that both anabolic steroid use as well as legal performance-enhancing substances is longitudinally associated with criminal offending.

Although anabolic steroid use was known to be associated with criminal offending, the possibility of a similar link between use of legal performance-enhancing substances, such as creatine, and criminal offending remained unknown. 

To address this, researchers analysed a sample of over 9000 US participants from the National Longitudinal Study of Adolescent Health (Add Health). The results show a need for more research on performance-enhancing substances to understand the complex social problems associated with their use.

“This is the first study to identify relationships between legal performance-enhancing substance use and criminal offending,” said lead author Kyle T. Ganson, PhD, MSW, assistant professor at the University of Toronto’s Factor-Inwentash Faculty of Social Work. “This finding is acutely salient because these substances are easily accessible and commonly used, particularly among young people.”

The study highlights the importance of clinical professionals screening for performance-enhancing substance use and assessing patterns of criminal offending among young people.

“We need more research to identify effective prevention and intervention techniques to ensure that we reduce the use of these substances, as well as curtail any connection with criminal offending,” said co-author Jason M. Nagata, MD, MSc, assistant professor at the University of California, San Francisco’s Department of Pediatrics.

“The associations found in this study are likely explained by an intersection of behavioral, psychological, and sociocultural influences,” says Ganson. “We therefore need to target this problem from a multitude of angles, including clinically and via public health and policy interventions.”

Source: EurekAlert!

Journal information: Ganson, K.T., et al. (2021) Performance-Enhancing Substance Use and Criminal Offending: A 15-Year Prospective Cohort Study. Drug and Alcohol Dependence. doi.org/10.1016/j.drugalcdep.2021.108832.

Categories : Cardiovascular DiseaseTags :

After a Stroke, Muscles Lose Basic ‘Building Blocks’

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Muscle sarcomeres (consecutive green lines), the smallest functional unit of muscle, from inside a living human. Credit: Northwestern University

In a new study of stroke patients, researchers have discovered that, in an attempt to adapt for an unusable arm, muscles actually lose sarcomeres — their smallest, most basic building blocks.

Patients that have suffered a stroke are often unable to use the arm on their affected side. Sometimes, they end up holding it close to their body, with the elbow flexed. Northwestern University and Shirley Ryan AbilityLab researchers found out why this happens.

Stacked end to end (in series) and side to side (in parallel), sarcomeres form the length and width of muscle fibres. By imaging biceps muscles with three noninvasive methods, the researchers found that stroke patients had fewer sarcomeres along the length of the muscle fibre, resulting in the muscle structure being shorter overall.

This finding is consistent with the common patient experience of abnormally tight, stiff muscles that resist stretching, and it suggests that changes in the muscle potentially amplify existing issues caused by stroke, which is a brain injury. The team hopes this discovery can help improve rehabilitation techniques to rebuild sarcomeres, ultimately helping to ease muscle tightening and shortening.

“This is the most direct evidence yet that chronic impairments, which place a muscle in a shortened position, are associated with the loss of serial sarcomeres in humans,” said senior author Wendy Murray. “Understanding how muscles adapt following impairments is critical to designing more effective clinical interventions to mitigate such adaptations and to improve function following motor impairments.”

Murray is a professor of biomedical engineering at Northwestern’s McCormick School of Engineering, a professor of physical medicine and rehabilitation at the Northwestern University Feinberg School of Medicine and research scientist at the Shirley Ryan AbilityLab. The research was completed in collaboration with Julius Dewald, professor of physical therapy and human movement sciences and of physical medicine and rehabilitation at Feinberg, professor of biomedical engineering at McCormick, and research scientist at Shirley Ryan AbilityLab.

Measuring just 1.5 to 4.0 micrometres in length, sarcomeres are made up of two main proteins: actin and myosin. When these proteins work together, they enable a muscle to contract and produce force. Even though previous animal studies have found that serial sarcomeres are lost from muscles after a limb is immobilised in a cast, the phenomenon had never before been demonstrated in humans. The animal studies found that the shorter muscles due to lost serial sarcomeres also became stiffer.

“There is a classic relationship between force and length,” explained first author Amy Adkins, a PhD student in Murray’s laboratory. “Given that the whole muscle is composed of these building blocks, losing some of them affects how much force the muscle can generate.”

To conduct the study in humans, the researchers combined three non-invasive medical imaging techniques: MRI to measure muscle volume, ultrasound to measure bundles of muscle fibers and two-photon microendoscopy to measure the microscopic sarcomeres.

Imaging opens new possibilities
Combining these technologies, the researchers imaged biceps from seven stroke patients and four healthy participants. As stroke patients are more affected on one side of their body, the researchers compared imaging from the patients’ affected side to their unaffected side as well as to images from the healthy participants.

In the stroke patients’ affected biceps, researchers found less volume, shorter muscle fibres and comparable sarcomere lengths. After combining data across scales, they found that affected biceps had fewer sarcomeres in series compared to the unaffected biceps. Greater differences between stroke patients’ arms than healthy participants’ arms were seen, indicating that stroke was the cause.

By combining medical imaging to better view muscle structure, the study also establishes that it is possible to study muscle adaptations in sarcomere number in humans. Prior to two-photon microendoscopy, human studies were limited either to examining dissected tissues in anatomy labs, which give imperfect insight into how muscles adapt to injury and impairment, measuring sarcomere lengths during surgery or from a muscle biopsy, which restricts who can participate in the study.

“In almost every facet of our world, there is an important relationship between how something is put together (its structure) and how it works (its function),” the researchers said. “Part of the reason medical imaging is such a valuable resource and clinical tool is that this is also true for the human body, and imaging gives us an opportunity to measure structure.”

Source: Northwestern University

Journal information: Adkins, A.N., et al. (2021) Serial sarcomere number is substantially decreased within the paretic biceps brachii in individuals with chronic hemiparetic stroke. PNAS. doi.org/10.1073/pnas.2008597118.