Nose cells as the key COVID-19 entry point

Sungnak et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature Medicine, April 2020.

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Detection of the virus was first reported in Wuhan, China and has since spread worldwide and emerged as a global pandemic. COVID-19 primarily affects the lungs and airways and has a wide range of symptoms including fever, coughing, and sore throat. One of the scariest aspects of the virus is that some people may not manifest symptoms but can still carry and spread it. In severe cases, the virus causes pneumonia that can ultimately lead to death. Studies suggest that the virus is thought to be spread through respiratory droplets produced when an infected person coughs or sneezes and appears to be easily transmitted within affected areas. COVID-19 has spread to more than 184 countries and claimed more than 190,000 lives so far. One of the major questions scientists around the world are trying to understand is how the virus spreads, how we can prevent transmission, and how we can develop an effective vaccine. To discover the target cells involved in COVID-19 transmission, scientists analyzed the gene expression profiles of thousands of cells from 20 different human tissues including the lung, nasal cavity, eye, gut, heart, kidney, and liver. They specifically looked for individual cell types that expressed both of two key COVID-19 entry proteins – the receptor protein ACE2 and the TMPRSS2 protease. These analyses revealed that mucus-producing goblet cells and ciliated cells on the inner lining of the nose have the highest level of COVID-19 virus proteins of all cells in the airways. While there are many external and internal factors that contribute to the virus’ transmissibility, these findings are consistent with the rapid infection rates of the virus. The location of these cells on the surface of the inside of the nose makes them highly accessible to the virus and also may assist with transmission to other people. Interestingly, ACE2 and TMPRSS2 were also found in cells in the cornea of the eye and in the lining of the intestine. This suggests another possible route of infection via the eye and tear ducts, and also revealed a potential for fecal-oral transmission. These findings have important implications for understanding viral transmissibility and could have critical translational implications. For example, given that nasal carriage is likely to be a key feature of transmission, drugs and vaccines administered intra-nasally could be highly effective in limiting the spread of the virus.

Neutrinos Could Explain Why the Universe Has So Much More Matter Than Antimatter

The T2K Collaboration. Constraint on the matter–antimatter symmetry-violating phase in neutrino oscillations. Nature, April 2020

The current laws of physics propose that 13.8 billion years ago, at the time of the Big Bang, every particle of matter had been created with a counterpart called antimatter. Antimatter is precisely the same as matter but with an opposite physical property such as an electrical charge. The great mystery for physicists is why there is so much more matter than antimatter in the universe. If there had been equal quantities in the beginning then each particle would have wiped each other out in a blaze of energy and left the universe full of just photons and dark matter. To understand the mystery behind this asymmetry, scientists have utilized an experiment known as “T2K.” T2K is a collaboration between 500 international scientists that employs a proton accelerator in Japan that generates beams of subatomic particles called muon neutrinos and antineutrinos which then travel 295 km to the gigantic Super-Kamiokande detector, located in a tank filled with 50,000 tons of water under a mountain in Kamioka on Japan’s west coast. During this trip, the muon neutrinos and antineutrinos change in flight to electron neutrinos and antineutrinos, demonstrating the phenomenon of neutrino oscillations. The team observed for the first time that there is a significant difference between neutrino and antineutrino oscillations. Neutrinos were found to turn into electron neutrinos at a much higher rate than their antineutrino counterparts and, as a result, would propagate regular matter at a higher rate than antimatter. These results show that although matter and antimatter look so similar to each other, they can behave completely different. Previously, scientists have found some differences in behavior between matter and antimatter versions of other subatomic particles called quarks, but the differences observed did not seem to be large enough to account for the dominance of matter in the universe. This new data indicates that subatomic particle neutrinos might be the very reason the universe is dominated by matter. While the scientific community is very excited about these results, most experts suggest collecting a lot more data in order to get the confidence level of their results up over the current ratio of 95%.

Humans Tend To Go With Our “Gut Feelings” Over Evidence-based Decisions

Konovalov& Krajbich. Mouse tracking reveals structure knowledge in the absence of model-based choice. Nature Communications, April 2020.

A new study showed that when faced with a decision, humans prefer to follow their “gut feeling” or habits instead of taking all facts into account. In the study, participants played a simple computer game in which identifying patterns could make them more money. While following the patterns led to success most of the time, there was still a 10-40% chance that it would not give the best outcome. The researchers observed that 56 of the 57 participants were able to identify the pattern to make the decision that gave them the highest chance of success. However, only about 20% of players consistently went with that choice after it failed them. The other 80% of players diverged and made choices based upon their gut feelings. The researchers suggest that participants decided to go with their gut feelings when making in-game decisions because choosing the best pattern only led to a slightly higher chance of success. This study highlights how decision-making works in real life. People can learn what choices lead to the best outcomes; but putting that knowledge into practice can often be difficult as it likely takes a lot of mental and sometimes physical energy to always make decisions based upon your knowledge of your current environment. Moreover, the rewards of following the best strategy aren’t always obvious in real life. Following a familiar strategy may increase your success by only a small percentage. In our decision making, there is always the dilemma – what we should do from a statistical perspective versus what worked out well recently, typically in an anecdotal manner.

Sometimes, your back itches slightly and scratching it at that perfect spot fills you with an odd sense of happiness. Other times, you notice a biting itch on your arm and a chickpea-like redness shows up there. Oh, those mosquitoes! It is rarely likely to catch a mosquito in the act, and sometimes it even feels as if their bites just appear out of thin air. As you scratch the blister to soothe the itchiness, your eyes scan the room to locate its infamous proboscis. You see it on a wall, plump with the blood it sucked from you. You cannot help thinking: Why do their bites always leave so much itching? Or even, what is the purpose of itching at all?

Itching is an unpleasant feeling we perceive by our skin and mucous membranes, and an occasionally uncomfortable and sometimes very excruciating feeling.

Itching, just like pain, is a sensation intrinsic to our body to protect itself [1].  It is the way our skin “talks” to us. Indeed animals, even fish, itch too. When itched, our skin instinctively and in its own tongue tells us, “There is something that bothers me and I want you to push it away from me immediately!” If it was not for itching, we would not notice a spider walking on our arm. We would not be disturbed by lice and scabies mites or even fungi that settled on our skin, and we would not try to protect ourselves from these pests either.

An ordinary scabies patient has an average number of about 15-20 adult scabies mites on their skin. In the case of Norwegian or crusted scabies, which is most commonly observed among the elderly, the bedridden, people with seriously weakened immune systems, or those who are unable to itch themselves sufficiently, there are thousands of parasites under the thick crusts of the skin [2]. Itching accelerates the blood circulation on the itched parts, and tissues virtually prepare to fight infection by the rushing blood cells and substances [3]. Yet, millions of people also suffer from chronic itching and scratch their itches much more than usual. To understand this, we need to set on a journey from our skin to our brain.

Human skin consists of three layers: epidermis, dermis and subcutis (also known as hypodermis). The dermis layer in the middle makes glove-like protrusions upward into the epidermis. At the top of these protrusions are mechanoreceptors and nerve endings that allow our skin to sense stimulus (such as temperature, sharpness, pressure, vibration, pain, or itching) [3]. With these receptors, our skin functions as one of our five sensory organs and more like an “alarm system” of our body against changing conditions outside. This alarm system has been created so perfectly that each component knows exactly what stimulus to detect.

Previously, it was thought that pain and itching were sensed by the same receptors (nociceptors) and that mild stimuli were responsible for itching while strong stimuli were responsible for pain [4]. Yet, a contradiction existed because while pain triggered an avoidance reflex, itching activated the scratching reflex. In recent years, it was discovered that the receptors (pruriceptors) that perceive the itching sensation on the skin are the free boundary terminations of C-fibers with myelin-free, slow conduction velocity extending in the form of tree branches toward the upper layer of the skin. Furthermore, it was found that the skin cells themselves behave like itch receptors [3, 4]. When we receive a stimulus that induces itching, such as a mosquito bite which leaves anticoagulant substances on our skin, the mast cells in the skin tissue spring to defense against those alien substances. This ensues the secretion of the bodily defense system called mediators, substances that are produced and stored by mast cells as precursor for emergency conditions. Histamine is the most known of these substances and is the most important mediator in itching conditions [5]. Histamine binds to receptors found for itself in myelin-free C fibers that are tasked for detecting itching on the skin. If we consider histamine as a key, the lock that it fits into is on the nerve that senses itching. Thus, the itching nerve is stimulated by histamine.

The nerves receiving this stimulus connect to the spinal cord at their respective levels and transfer the message to another nerve. Each of these transfer processes is mediated neurotransmitters. The last message transmitted to the brain through these nerves is assessed by the brain and labeled as “itching” [6]. The brain determines the coordinates of the itching location and orders the scratching action to the related muscle system. A new journey that conveys messages from the brain to the arm muscles ends with scratching. Considering the swift rubbing action when we feel an ant walking on our face and scratch to push it away, we may value how fast and perfect our brain and transmission system work.

It is also rather odd how soothing itching can be despite its initially uncomfortable feeling, almost as if our body is rewarding us for saving it from a threat. There are several reasons for this contradiction. Scratching causes a low-intensity pain on the skin. Pain and itch are positioned on the skin alternately. The transmission of the sensation of pain is prioritized while the transmission of itching is prevented [7]. Consequently, our brain senses the pain and, in response, secretes the hormone called serotonin to soothe the body. Although this makes us feel relaxed for a short time, the brain continues to transmit virtual sense of itching by connecting to the receptors that are located on the spinal cord along the same nerve path with the receptors for serotonin [8]. This condition, which may be termed as a vicious cycle of itching-scratching, unsurprisingly infuriates patients. Scratching the same area on the skin continuously causes the production of new mediators and oversensitivity of itching nerves, which can thus turn itching into a chronic distress. Chronic itching can often result as a complication from skin diseases such as scabies, lice, eczema, fungal diseases, or drug allergies. It can also result from a systemic disease such as chronic renal failure, cholestatic liver diseases, thyroid problems, iron deficiency anemia, blood diseases and, rarely, cancers [7]. Itching in systemic diseases can be triggered by mediators on the skin but also by neurotransmitters in the intermediate pathway. This kind of itching cannot be controlled by drugs called antihistamines which block the histamine pathway. Sometimes the brain will receive false itching alarms due to post-shingles contraindications or nerve damage in the vertebrae. Such episodes of itching need to be addressed to prevent adverse outcomes. At times, the reason an itch can occur can even be psychological when there seems to be no need for an itch. According to research, scratching activates the brain’s reward center which triggers the addiction mechanism. Patients in that case are thrilled as they itch constantly [9].

As doors in this mysterious journey of science are opened one after another, we discover that nothing has been created without a purpose, including apparently discomforting sensations such as itching, which, it turns out, is how our skin communicates with us!

References

1. Arıcan O. Kasintinin patofizyolojisi, klinigi ve tedavisi Turkderm 2005;39(2):88-97
2. Jonston G, Sladden M. 2005 Scabies: diagnosis and treatment BMJ;17;331(7517):619-22
3. Guyton AC, Hall JE. Tıbbi Fizyoloji 10. Baski 2001.p815-42
4. Schmelz M. Itch and pain. Neurosci Biobehav Rev 2010;34(2):171-6
5. Arck P, Raus R. From the Brain-skin connection. Neuroimmunomodulation 2006;13(5-6)347-56
6. Metz M, Stander S. Chronic pruritus pathogenesis clinical aspects and treatment. J Eur Acad Dermatol Veneral 2010;24(11)1249-60
7. Metz M, Grundman S, Stander S. Pruritus: an overview of current concepts. Vet Dermatol 2011;22(2):121-31
8. Chen ZF et all. Descending control of itching transmission by Serotonergic System via 5-HT1A-facilitated GRP-GRPR signaling. Neuron Vol.84(4) Nov.19-2014

9. Chan YH et all. Brain’s Reward Circuits Mediate Itch Relief. A functional MRI Study of Active Scratching. Dec. 2013

ATM is currently one of the most attractive technologies in the digital data communications field. In ATM, information is transmitted in short fixed-length blocks that are called cells (Figure 1). An ATM cell consists of a header and a data field that carries the actual information-either video, voice or data. The cell header contains a label denoting the routing address.

Not only was ATM created to overcome the difficulties in existing transfer methods but also to allow the creation of a Broadband Integrated Service Digital Network (B-ISDN).

Transmission speeds up to the physical limits (e.g., 622.05 Mbps signaling rate nowadays) are achievable with ATM. By contrast, there are limitations to the upgrading possible, with the most popular traditional Local Area Network (LAN) topologies (e.g., Ethernet and Token Ring), to higher bandwidth, which means incapacity to support current and of course future real-time applications.

Although the connection-oriented ATM was initially designed for Wide Area Networks (WANs), its unique features including flexibility, scalability, high transfer capacity and support for multimedia applications, also fired the imagination of the LAN vendors in the early 1990s. Since ATM is suitable for both LANs and WANs, historical separation of traditional LANs that are connectionless and WANs that are connection-oriented will eventually disappear. This will form a universal platform for data communications as well as replace the conventional LAN topologies. With full deployment of ATM in design, manufacturing and maintenance of the future networks, the overall costs will be relatively smaller.

The traditional LANs use a shared media-access (e.g. bus) method. That means all stations of the network have to share one transmission medium and have to contend for access. The limitations of shared media-access method are overcome by the ATM’s new approach of switching systems based on central media-access management (Figure 2). Since each user has a dedicated connection to one of the ATM switch ports, users no longer need to contend for access as opposed to the legacy LANs. Moreover ATM LAN users are provided WAN services through another port on the LAN switch. On the other side, the traditional LANs have no direct wide-area capabilities-they must depend on a separate piece of equipment to convert the LAN rates and protocols into WAN-compatible format.

Problems that arise in transmission through the current networks of voice, video and data simultaneously (or in real-time) could well be prevented by using ATM.

With its low-cost networking and technology ATM will soon provide scientist and engineers greater global freedom to exchange data, images (e.g., medical imaging applications) and models in real-time. Beyond the physical boundaries of classrooms, students (especially disabled) will be able to be part of a class and interact with others just as though they were there using high-speed and reliable ATM networks.

GLOSSARY

B-ISDN: A high-speed (above 1.544 Mbps signaling rate) network standard that grew from traditional narrowband ISDN.

Connection-oriented: A network (e.g., WANs) that establishes, either permanently or on a call-by-call basis, a specific circuit path for transmission.

Connectionless: A network (e.g., legacy LANs) in which no particular path is established for the transfer of information.

Ethernet: A LAN using 10 Mbps signaling rate.

LAN: High-speed network connecting personal computers, printers, and other data equipment within an office or campus.

Mbps: Mega bit per second

Token Ring: A LAN using 4 or 16 Mbps signaling rate.

WAN: High-speed network connecting communications equipment nationally and internationally.

References

• PARULKAR G. M.: ‘Local ATM Networks’, IEEE Network March 1993, p.S-9.
• VENIERIS I. S., ANGELOPOULOS J. D. & STASSINOPOULOS G. I.:
• ‘Efficient Use of Protocol Stacks for LAN/MAN-ATM Interworking’, IEEE Journal on Selected Areas in Communications October 1993, 11(8) p.1160-1170,.
• KIM B.G. & WANG P.: ‘ATM Network: Goals and Challenges’, Communications of the ACM February 199538 (2), pp. 39-44.
• The ATM Forum: http:/ /www.atmforum.com/