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Glaucoma treatments; are new developments hiding in plain sight?

Written by Olivia Kingston

Glaucoma is the leading cause of irreversible blindness worldwide (1). As patients age, cells in the eye gradually deteriorate, causing patients to eventually go completely blind. Scientists at Liverpool University believe that by replacing these non-working cells with working ones, vision loss may be prevented!

What’s happening in glaucoma?

how glaucoma works
Figure 1. Pathophysiological changes in the eye as a result of elevated pressure in glaucoma. A schematic diagram showing how elevated intra ocular pressure in glaucoma puts pressure on the lamina cribrosa, causing tissue deformation and damage to optic nerve axons. Image based upon description and diagrams in Quigley, 2011.

Our eyes are filled with fluid, known as aqueous humour, that is constantly filtered by a tissue called the trabecular meshwork (2). In glaucoma, the cells that make up this tissue decrease in numbers and those remaining don’t function as they should do (3). This prevents the fluid from moving through the meshwork as it becomes stiffer and blocked by debris, causing pressure in the eye to increase (4). This pressure damages axons of the optic nerves preventing signals that contain visual information being sent to the brain (5).

Treating Glaucoma Today

Currently glaucoma treatments involve laser treatments or surgery to create channels for the fluid to drain out of the eye and reduce pressure, which unfortunately aren’t always effective (6). If the lost cells of the trabecular meshwork in glaucoma patients could be replaced with healthy cells, then the trabecular meshwork may be able to function normally and regulate pressure in the eye.

schematic diagram illustrating the pathway of aqueous humour. Important in regulating pressure in the eye.
Figure 2. The main aqueous humour outflow pathway via the trabecular meshwork into Schlemm’s canal. A schematic diagram showing the outflow pathway of aqueous humour. Aqueous humour is created at the ciliary body and flows into the anterior chamber and through the trabecular meshwork. Image and information from in Goel et al., 2010.

Hiding in plain sight?

The problem lies in how to develop these working cells and get them to where they need to be? Well, recent scientific discoveries find that these cells may be “hiding in plain sight”.

By changing the environment in the trabecular meshwork, we may be able to make use of cells already present in the eye, that have a unique ability to develop into specialised cell types, stem cells (7). In the right conditions, these stem cells can be encouraged to grow into healthy and functioning cells that could aid in aqueous humour outflow. What scientists need to know, is what changes are needed to make this happen…and that’s what is currently being investigated at Liverpool University!

Think of it like gardening. Flower seeds buried deep in dry and old soil, won’t blossom anytime soon. But if you replace the soil with fresh, nutritious compost and plenty of water you’ll have a flourishing garden. By finding the right compost and supplying water, scientists can replace non-working cells with healthy ones, without having to transplant new cells into patients.

Olivia Kingston is a PhD student studying glaucoma.

References

  • Liu, B. et al. (2018) ‘Aging and ocular tissue stiffness in glaucoma’, Survey of Ophthalmology. Elsevier USA, pp. 56–74. doi: 10.1016/j.survophthal.2017.06.007.
  • Tamm, E. R. (2009) ‘The trabecular meshwork outflow pathways: Structural and functional aspects’, Experimental Eye Research. Academic Press, pp. 648–655. doi: 10.1016/j.exer.2009.02.007.
  • Liton, P. B. et al. (2005) ‘Cellular senescence in the glaucomatous outflow pathway’, Experimental Gerontology. NIH Public Access, 40(8–9), pp. 745–748. doi: 10.1016/j.exger.2005.06.005.
  • dysregulation in glaucoma’, Experimental Eye Research. Academic Press, pp. 112–125. doi: 10.1016/j.exer.2014.07.014.
  • Quigley, H. A. (2011) ‘Glaucoma’, The Lancet, 377(9774), pp. 1367–1377. doi: 10.1016/S0140-6736(10)61423-7.
  • Weinreb, R. N., Aung, T. and Medeiros, F. A. (2014) ‘The pathophysiology and treatment of glaucoma: A review’, JAMA – Journal of the American Medical Association. American Medical Association, pp. 1901–1911. doi: 10.1001/jama.2014.3192.
  • Yun, H. et al. (2016) ‘Stem cells in the trabecular meshwork for regulating intraocular pressure’, Journal of Ocular Pharmacology and Therapeutics. Mary Ann Liebert Inc., 32(5), pp. 253–260. doi: 10.1089/jop.2016.0005.
  • Goel et al. (2010) ‘Aqueous Humour Dynamics; A Review’, The Open Opthamology Journal. 4(1) pp 52-9. doi: 10.2174/1874364101004010052.

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COVID-19 Infographics PPE

Types of face masks

Here is our quick overview to the different types of face masks available.

N95/N100 and FFP2/FFP3 Masks

  • N95/N100 designations are used in the USA and are roughly equivalent to FFP2/FFP3 in the EU.
  • FFP3/N100 masks are the highest rated masks available, and protect the wearer from aerosols and droplets at concentrations up to 50X occupational exposure limits (set by health organisations).
  • These are needed and used by medical professionals in direct, frequent contact with patients known to have an infectious respiratory disease.

Surgical Masks

  • Surgical masks protect the wearer in a similar way to N95/FFP2 masks, however they are less effective than these.
  • They will protect the wearer from respiratory droplets which may approach the face, however are fitted less firmly to the face and filter less effectively than an N95.
  • These are being used by medical professionals as a precaution when treating any patient, in case they may also be an asymptomatic carrier in addition to their presenting medical complaint.

Home-made Masks

  • Home-made masks are not regulated or confirmed to protect to any given standard.
  • However, if the majority of people wear a mask of some form, evidence shows a reduction in disease spread.
  • This is particularly important for people who may have asymptomatic infections and not know that they are spreading the virus while out of the house.
  • Any time you are outside the house in an enclosed or crowded space you should wear a face covering if you can – this includes supermarkets and public transport.

Why did the advice change suddenly?

Research!

Remember we are forever learning: advice and guidance will evolve as we learn new things.

Previously, home-made masks were not advised, as they are less protective than medical masks and individually do not provide full protection to the wearer.

However, new research is now showing that the limited protection given through reducing droplet spread from the wearer is worth it. In addition, the net gain of everyone wearing one is much greater than just the actions of one single person.

This was a guide on the types of face masks…

COVID-19 Infographics PPE

Do face masks with valves protect others from me?

Do face masks with valves protect others from me? No

😷 Evidence for wearing face masks when in close contact with others is still growing – but make sure to be selective with what you use to protect yourself and others as much as possible!

💨 Masks with a valve that lets air out might feel more comfortable, but they reduce the efficiency of the mask’s protection.

💦 This reduction in efficiency can let respiratory droplets from you fly towards others, risking infecting others if you are infected and don’t have symptoms.

🦠 To protect yourself and those around you, stick to masks without a valve – even homemade cotton masks are effective at stopping droplets!

Check out our previous post on PPE for more info:

Do face masks with valves protect others from me?

How does it work? Infographics

The immune system: an introduction

What makes up my immune system??

Our immune systems can use different approaches to protect us against invaders, but what are these approaches and how do they work?

Here is our simple summary, including:

  • The primary immune response, also known as the innate immune response.
  • The secondary immune response, also known as the adaptive immune response.
  • The cells involved, such as phagocytes, B-cells, antibodies and T-cells
  • What is long term immunity?

First glance or round two?

The first time you are exposed to a disease-causing organism (like a virus or bacterium), your body launches its primary immune response. This response is generic and can be used against any pathogen you come into contact with – a bit like using a citronella candle to keep away all bugs.

The second time you are exposed to that organism, your body has learned about it and can launch a more targeted, secondary immune response on it. Often this means you don’t even get infected or feel unwell – this is more like using a specific anti-mosquito spray.

Phagocytes and the innate immune response

Phagocytes are important cells that are part of the general, first line of defence. These cells sniff out the chemicals left behind by bacteria as they travel through the body, and “eat” the bacteria to destroy them. Very much like an immune system pac-man.

In addition to these cells, the body can also employ methods like a fever – while you do feel poorly, higher body temperatures improve the efficiency of immune cells and may slow down pathogens.

B Cells and Antibodies

B Cells are super important in helping a body remember pathogens you’ve come into contact with before. If you are reinfected with the same pathogen, B cells recognise it from molecules on its surface and warn the rest of the immune system about its presence.

B Cells also produce plasma cells, which in turn release antibodies. Antibodies are specific to one particular pathogen, and fit them like a key to a lock. They are either attached on cells, or flow freely in the blood.

T Cells

T Cells come in two forms: helper cells and killer cells. Helper cells release molecules that help other cells to recognise and track the pathogen around the body. Killer cells track down the cells of your body that are infected with the pathogen and release chemicals to remove those cells to stop further infection and spread.

Long term immunity

Although your body has these cells that remember pathogens you have encountered before, they are not always for life. Some pathogens can mutate to get around the immune memory, and other times your body’s response will dwindle over time.

This is different for each potential infection, and is the reason why people can have the same illness twice, or why some vaccines need booster shots.

Equally, some of the knowledge from one disease can sometimes be applied to related pathogens if they are similar enough. This is known as cross-reactivity and can sometimes mean you get less sick the first time you encounter a pathogen.

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Science News: 14th of July

SCIENCE NEWS 🧪 ⁣

The news in science this week, as always, curated by Serat @touchthebeardagain ✨ ⁣

🔍 COVID-19 autopsies reveal insight into coronavirus deaths and the role of an individuals immune system ⁣

☠️ Iron Age remains have been discovered following HS2 excavation, the remains are a bit of a mystery!⁣

🧠 End of life patient’s brains respond to sound even in an unconscious state, providing rationale for the observed comfort loved ones voices give ❤️

Would you like to know more about these topics? Or simply join in the conversation about them – get in touch!

Blog DiMeN Blog

Could Taking the Pee be the Future of Understanding Rare Genetic Kidney Diseases?

Written by Rebecca Dewhurst @becky_dewhurst from the @SayerLab

How can urine help us understand kidney diseases?

Everyday thousands of healthy kidney cells are shed into our urine. Under the right conditions, these cells, known as urine-derived renal epithelial cells, or hURECs for short, can be collected as a liquid biopsy, and used to study a wide range of rare genetic kidney diseases without a traditional painful invasive biopsy.

isolating kidney cells from urine to study kidney diseases
Figure 1. Simplified method of isolating and culturing human urine-derived renal epithelial cells (hURECs).

What do the Kidneys do?

The kidneys are bean shaped organs found towards the back of the upper abdomen involved in the ultrafiltration of our blood. Our kidneys are vital in maintaining appropriate water levels, and produce waste products like urea which is excreted in urine.

Who is affected by kidney disease?

In the UK alone, one in ten people have Chronic Kidney Disease (CKD); this equates to around 3 million patients in total (1). There are a number of reasons for the onset of kidney disease, including poor control of blood sugar levels in diabetes, high blood pressure or inherited causes.

What diseases can we study using these cells?

In our Newcastle University Renal Genetics group, we predominantly study a group of diseases known as ciliopathies, which occur due to cilia defects. Found on the surface of almost all cells, cilia are finger-like protrusions acting like radio antennae feeding information back to the control centre of the cell, known as the nucleus. Ciliopathies can affect a number of organ systems, including the eyes, brain, liver and kidneys. Examples of ciliopathies affecting the kidneys include Joubert Syndrome, Oral-facial-digital Syndrome, Nephronophthisis and Autosomal Dominant Polycystic Kidney Disease, all of which we can study using hURECs.

Figure 2. Basic structure of a primary cilium. Cilia are finger-like protrusions which are found on the surface of almost all cells, and are involved in key cellular signalling processes. Ciliopathies can result in extra-long, short, or curly cilia. Figure adapted from (2).

How have these cells been used?

For many years, the Newcastle University Renal Genetics group we have been using hURECs to further understand how and why kidney disease develops in ciliopathies like Joubert Syndrome (3; 4) and Nephronophthisis (5). These hURECs allow us to investigate both the phenotype (characteristics that we can see) and the genotype (the genetic blueprint including genes and DNA) which are involved in renal ciliopathies, giving much desired answers to patients and their families.

Remarkably, hURECs have been used in our hands to generate 3D cell models known as organoids which can be considered as ‘kidneys in a dish’. These renal organoids, known as tubuloids (6) or nephrospheres (7), have allowed for more complex kidney disease modelling.

Figure 3. Images of human urine-derived renal epithelial cells (hURECs) from Wild Type and Joubert Syndrome urine samples. Cell nuclei are shown in blue with cilia shown in green. Image taken, with permission from  (4).

What does this mean for patients?

One of the main benefits of using hURECs is that we can gain a kidney organ specific snapshot of how the renal cilia are affected, which can sometimes be missed using other cell types like fibroblasts, which are derived from skin biopsies. Urine sample collection in order to grow hURECs is also quick, easy and most importantly pain free, meaning multiple samples can be taken.  Exciting opportunities in the development of patient-specific hUREC generated disease models highlight why urine samples, a waste product, may hold the key to developing our understanding of kidney diseases.  

References

1. Kidney Research UK. Annual Reports and Accounts. Kidney Research UK. [Online] 2020. [Cited: 26 06 2020.] https://kidneyresearchuk.org/about-us/annual-reports/.

2. Ciliopathies: an expanding disease spectrum. Waters, A M and Beales, P L. 7, 2011, Pediatric Nephrology, Vol. 26, pp. 1039-1056.

3. A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies. Srivastava, S, et al. 23, 2017, Human Molecular Genetics, Vol. 26, pp. 4657-4667.

4. Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model. Ramsbottom, S A, et al. 49, 2018, PNAS, Vol. 115, pp. 12489-12494.

5. Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants. Molinari, E, et al. 2018, European Journal of Human Genetics, Vol. 26, pp. 1791-1796.

6. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Schutgens, F, et al. 2019, Nature Biotechnology, Vol. 37, pp. 303-313.

7. Urinary nephrospheres indicate recovery from acute kidney injury in renal allograft recipients – a piolet study. Knafl, D, et al. 251, 2019, BMC Nephrology, Vol. 20.

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Sir Alexander Fleming
A Sip of Science History Infographics

Sir Alexander Fleming: A sip of science history

A Sip of the Past… This week we focus on Sir Alexander Fleming 👨‍🔬. The man who discovered the well known antibiotic, penicillin.

Sir Alexander Fleming discovered penicillin in 1928. His discovery allowed for further research, development and purification of penicillin alongside scientists Howard Florey and Ernst Chain. Their collaboration was recognised when they shared the 1945 Nobel Prize in Physiology or Medicine and the use of penicillin has since saved millions of lives around the globe.

⏩ Swipe through to find out more about the man behind the breakthrough!

More Science History

References
Blog DiMeN Blog Research Summaries

‘Humanised’ worms for the discovery of new anti-epileptic drugs

Written by Lucy Job: https://www.linkedin.com/in/lucyjob/

Caenorhabditis elegans is a type of tiny soil-dwelling worm, found to accept certain human genes into their own genome [1]. These ‘humanised’ worms are a very useful tool to study human disease, with researchers at the University of Liverpool now using them to study human epilepsy and discover new anti-epileptic drugs [1] [2].

“C. elegans, model organism in life sciences” by ZEISS Microscopy

What is epilepsy?

Epilepsy is one of the most common conditions affecting the brain, shaping the lives of an estimated 50 million people worldwide [3]. In the UK alone, there are an estimated 600,000 epilepsy patients, which is almost 1 in every 100 people, with 87 people diagnosed every day [4]. There are a lot of different causes of epilepsy, and it can affect people of all ages [5].

Known causes of epilepsy, adapted from the World Health Organisation Infographics of Epilepsy [5]

Those with epilepsy suffer from recurrent seizures, which is caused by sudden bursts of electrical activity within the brain. The most well-known seizure type affects movement, causing muscle jerking, twitching, and/or weakness. Lesser known seizures affect the person’s awareness to their surroundings and can cause changes in sensation or emotion [6].

Currently, there are over 20 anti-epileptic drugs available with many different drug targets [7]. These drugs try to stop the sudden uncontrolled bursts of electrical activity within the brain. However, these anti-epileptic drugs do not work for one third of patients, named ‘refractory epilepsy’, with the reason for this not fully understood [8]. Therefore, new drugs are desperately needed for those patients with refractory epilepsy.

Why worms for drug development?

Making new drugs is controversial as testing on mammals, like mice and primates, has many ethical and financial issues. As these worms are invertebrates, less complex animals, they do not require extensive ethical training for use [9]. Also, these worms have a short reproduction time (~3 days) and lifespan (~3 weeks) and do not need expensive equipment take care of them, making them a much cheaper alternative [10]. Therefore, it is beneficial to test new drugs on less complex animals first, and then move onto more complex animals later in the drug development process. However, it is hard to justify using tiny soil-dwelling worms to test drugs for humans when we are so different [9].

Humanising the worm

To tackle this, researchers led by Professor Alan Morgan at the University of Liverpool have created humanised worms to study severe forms of epilepsy, such as Ohtahara syndrome [1]. This was achieved, in part, using the highly specialised gene editing process CRIPSR-Cas9 and which is used to insert, delete, or substitute target genes, to fix or introduce gene mutations [11].

Brief summary of CRISPR-Cas9. The Cas9 enzyme cuts the target genetic code, causing a DNA break. Once broken, a DNA repair process, leads to the desired insertion, deletions, or substitution at the target site.

GABA is a neurotransmitter (a biological chemical) which can prevent sudden electrical activity in the human brain. Studies by multiple different research teams have found GABA mutations (more specifically GABAA receptors) in patients with a spectrum of epileptic encephalopathies, such as Lennox-Gastaut syndrome and West syndrome [12].

In this project we aim to introduce mutated human GABAA receptor genes found in epilepsy patients into worms. We will then induce seizures in the worms and test a range of new anti-seizure drugs to see which compounds are most effective. Therefore, we will be able to assess the effect the new anti-seizure drugs may have in humans with the same genetic mutations.

Humanised worms used to study anti-epileptic drugs at the University of Liverpool.

Using these humanised worms as a first step in drug development is beneficial as it gives researchers the opportunity to fast-track the selection process, whittling down large numbers of drug candidates to a select few in a short space of time [2].

References

1.              Zhu, B., et al., Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans. Epilepsia, 2020. 61(4): p. 810-821.

2.              Wong, S.Q., et al., A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action. J Neurosci Methods, 2018. 309: p. 132-142.

3.              Organization, W.H., Epilepsy: a public health imperative. 2019: World Health Organization,.

4.              Action, E. What is epilepsy? 2019 2019 [cited 2020 29.06.2020]; Available from: https://www.epilepsy.org.uk/info/what-is-epilepsy.

5.              Organization, W.H. Infographics on epilepsy. 2016-2017  [cited 2020 29.06.2020]; Available from: https://www.who.int/mediacentre/infographic/mental-health/epilepsy/en/.

6.              NHS. Symptoms – Epilepsy. 2017  [cited 2020 29.06.2020]; Available from: https://www.nhs.uk/conditions/epilepsy/symptoms/.

7.              Loscher, W., et al., New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov, 2013. 12(10): p. 757-76.

8.              Kwan, P. and M.J. Brodie, Early identification of refractory epilepsy. N Engl J Med, 2000. 342(5): p. 314-9.

9.              Cunliffe, V.T., et al., Epilepsy research methods update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms. Seizure, 2015. 24: p. 44-51.

10.            Chen, X., et al., Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases. Chem Cent J, 2015. 9: p. 65.

11.            Zhang, F., Y. Wen, and X. Guo, CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet, 2014. 23(R1): p. R40-6.

12.            O’Reilly, L.P., et al., C. elegans in high-throughput drug discovery. Adv Drug Deliv Rev, 2014. 69-70: p. 247-53.

13.            Hernandez, C.C. and R.L. Macdonald, A structural look at GABAA receptor mutations linked to epilepsy syndromes. Brain Res, 2019. 1714: p. 234-247.

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  1. The COVID-19 Vaccine Landscape
  2. Back to school. What do the students think? 49% of students say no.
  3. Natural or Nasty? Traditional Chinese Medicine and COVID-19
COVID-19 Infographics PPE

Lockdown eases, but the virus has not gone away.

Post originally on instagram

So things are opening up again this weekend (4th of July 2020) in the UK. The lockdown eases.

It is everyones individual choice where they wish to go now and what they want to do – if you are looking for ways to reduce risk while going out and seeing friends, here are some science-based suggestions:

Effective hand washing is still extremely important! Make sure you’re washing frequently and efficiently!

 Masks are still growing in evidence for their effect in slowing disease transmission. When you’re in close contact with people outside of your household, consider wearing one as often as you can!

Check out yesterday’s post for how to put on and wear your mask safely!

If possible, meet outdoors! Respiratory droplets have a reduced risk of reaching the people you’re with if you’re outside – a walk or a picnic are good alternatives to a sit-down meal.

Reduce the number of people you see in short spaces of time. By distancing the different groups you see you can reduce the number of potential infections in a social group.

Do you feel ready for when lockdown eases? Let us know your thoughts – info@thesciencesocial.com

lock down eases
lockdown is easing
The current state of cases
social distancing, hand washing and PPE advice for when lockdown eases
Meet outside when you can
Reduce the number of interactions in short spaces of time
second wave
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Infographics The Science Social News

Science News: 1st July 2020

‼️ SCIENCE NEWS ‼️

This week’s news in science brought to you by Serat @touchthebeardagain .

👩‍🔬 Scientists have developed a portable 30 minute COVID-19 testing machine

🦠 The 10th Ebola outbreak in the Democratic Republic of Congo has been declared over.

🧠 University of Liverpool lead a neuro-surveillance study to assess how COVID-19 affects brain function

🍭 Common food additive used in sweets has been found to have adverse effects

For a brief history of Ebola and details on the most recent Ebola outbreak, read our blog post here.

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