How to Write a Research Paper

In high school, I took something called “Experimental Biology” where all we did was to do experiments and write papers. The culmination of this class was a giant “research” paper based on citations we looked up, old-style via microfiche, on the bacteria we grew in the lab. It took forEVER to find 3 articles on the bacteria I was working with. I will never forget the final, which was a set-up question for a paper written on the fly, in research paper style, during the 3 hours’ final exam time we were given. I was lucky. I had many classes that taught me how to write, two of which were in high school (I took creative writing as well). My old alma mater forced all freshmen to take a “How to Write a Paper” class and you had to pass it or else you spent the rest of eternity taking that class until you did. Thank god I passed the first time ’round.

For the people who aren’t so lucky, I found one (of many) helpful sources: Writing a scientific article: A step-by-step guide for beginners. And for those who want more sources, this paper has some citations to check out.

Brain on a Chip

In physiology, you learn that cells work with electricity. Action potentials were studied in every physiology class. A while ago, I read that scientists connected a neuron to a computer chip. Today, I wondered: what is the state of that research now? Well, a quick visit to Pub Med (I swear I use Google just a little bit more than I use Pub Med) showed that things were going along.

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases

By the way, there are tons of articles about the blood-brain-barrier on a chip (lab-on-a-chip) to study how we can treat diseases of the brain more effectively (because it’s hard to get drugs to go through the BBB as it is neuroprotective). I remember that the first question on the first homework I ever did for neuroscience class was about the BBB. So, very important stuff. For me personally, and if I’m still alive, this research can help find more efficient ways for less medication to work in my brain.

Then there is brain computer interface, which is also highly fascinating but now I’ve run out of time to write and will have to look at the topic later.

Diseases and syndromes I looked up in October

Microscopic polyangiitis – This disease, now known as microscopic polyangiitis (MPA), is a primary systemic vasculitis characterized by inflammation of the small-caliber blood vessels and the presence of circulating antineutrophil cytoplasmic antibodies (ANCA). Typically, microscopic polyangiitis presents with glomerulonephritis and pulmonary capillaritis, although involvement of the skin, nerves, and gastrointestinal tract is not uncommon. 

Thygeson’s Superficial Punctate Keratopathy – Thygeson’s superficial punctate keratitis (TSPK) is reportedly a rare disease with an insidious onset, numerous remissions and exacerbations, and a long duration. The corneal lesions are elevated, whitish–grey in colour, and granular in the intraepithelium. 

Acute Eosinophilic Pneumonia – this wasn’t for work. Actually, I was diagnosed with this once a long time ago. I have no idea if this is related, but I found out recently (within the past 10 years) that I have eosinophilic asthma.

Stuff I looked up in August & September

Lots of things these past 2 months! When I was in high school, someone (probably one of my high school teachers) told me that to earn your PhD you have to contribute to some field’s research with a new idea. At that time I thought, wow, that sounds really hard. I couldn’t imagine any new ideas. Then I got older and learned more. One thing I keep realizing is that the more you look things up and learn, the more you realize what you, or we as humans, don’t know. The hunt for answers only brings up more questions. Can we ever really know everything?

Moyamoya disease

Hyperproliferative lymphocytosis

Hereditary hemorrhagic telangiectasia

Todd’s paralysis – Todd’s paralysis is a neurological condition experienced by individuals with epilepsy, in which a seizure is followed by a brief period of temporary paralysis. The paralysis may be partial or complete but usually occurs on just one side of the body. The paralysis can last from half an hour to 36 hours, with an average of 15 hours, at which point it resolves completely. Todd’s paralysis may also affect speech and vision. Scientists don’t know what causes Todd’s paralysis.

Li-Fraumeni Syndrome – Li-Fraumeni syndrome (LFS) is an inherited familial predisposition to a wide range of certain, often rare, cancers. This is due to a change (mutation) in a tumor suppressor gene known as TP53. The resulting p53 protein produced by the gene is damaged (or otherwise rendered malfunctioning) and is unable to help prevent malignant tumors from developing. Children and young adults are susceptible to developing several multiple cancers, most notably soft-tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinoma and acute leukemia.

Sclerosing mesenteritis – Sclerosing mesenteritis, also called mesenteric panniculitis, occurs when the tissue (mesentery) that holds the small intestines in place becomes inflamed and forms scar tissue. Sclerosing mesenteritis is rare, and it’s not clear what causes it.

PMS2-related Lynch syndrome – In humans, the importance of MMR is underscored by the discovery that a single mutation in any one of four genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is an autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers.

Mevalonate kinase deficiency – Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disorder. Autoinflammatory syndromes are a group of disorders characterized by seemingly random or unprovoked episodes of inflammation generally due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.

Muckle Wells syndrome – Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash and joint pain.

Adult onset Still’s disease – Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder that can affect the entire body (systemic disease). The cause of the disorder is unknown (idiopathic). Affected individuals may develop episodes of high, spiking fevers, a pink or salmon colored rash, joint pain, muscle pain, a sore throat and other symptoms associated with systemic inflammatory disease.

Creatine in seniors

Sarcopenia is associated with reduced bone mass and bone strength and may be a contributing factor for the increased risks of falls and fractures often observed in aging adults. It is well established that resistance training is an effective lifestyle intervention for improving aging muscle mass, strength and bone accretion. Accumulating evidence indicates that creatine supplementation, with and without resistance training, has possible anti-sarcopenic and anti-dynapenic effects. Specifically, creatine supplementation increases aging muscle mass and strength (upper- and lower-body), possibly by influencing high-energy phosphate metabolism, muscle protein kinetics and growth factors. Creatine supplementation has shown potential to enhance bone mineral in some but not all studies, and seems to affect the activation of cells involved in both bone formation and resorption. Creatine has the potential to decrease the risk of falls experienced by aging adults which would subsequently reduce the risk of fracture. Finally, preliminary evidence suggests that creatine may have anti-inflammatory effects during times of elevated metabolic stress, such as during extended/intense aerobic exercise. 

Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation

I have this giant bottle of Naked Creatine (I got it from Amazon) and I feel that it helps me retain and build muscle just a bit better, as long as I don’t forget to put it in my smoothies. Starting last week, I started to put ~5 grams of creatine into my mom’s protein smoothie, because there seems to be a generally positive effect of creatine use in adults. There’s some research into this topic.

NASA is a busy place

I’m reading NASA’s launch schedules and it is fascinating!

Artemis I will be the first integrated test of NASA’s deep space exploration systems: the Orion spacecraft, Space Launch System (SLS) rocket and the ground systems at Kennedy Space Center in Cape Canaveral, Florida. The first in a series of increasingly complex missions, Artemis I will be an uncrewed flight test that will provide a foundation for human deep space exploration, and demonstrate our commitment and capability to extend human existence to the Moon and beyond.

… the DART spacecraft will slam into the asteroid Dimorphos at roughly 4 miles per second, attempting to slightly change the asteroid’s motion in a way that can be accurately measured using ground-based telescopes. The world’s first full-scale mission to test technology for defending Earth against potential asteroid or comet hazards…

The first flight of NASA’s X-57, a small, experimental airplane powered by electricity…

All of these can be found on the Upcoming Mission Events page.

Research articles on protein supplement or wine effects on health

Note: these are only a handful of studies compared to the multitudes of results I found on each topic. Please read widely to form a balanced perspective.

Effect of whey protein on blood pressure in pre‐ and mildly hypertensive adults: A randomized controlled study.

Moderate red wine consumption and cardiovascular disease risk: beyond the “French paradox”.

Effects of Whey and Pea Protein Supplementation on Post-Eccentric Exercise Muscle Damage: A Randomized Trial.

Effects of Whey Protein Supplementation Pre- or Post-Resistance Training on Muscle Mass, Muscular Strength, and Functional Capacity in Pre-Conditioned Older Women: A Randomized Clinical Trial.

Protein Intake and Exercise-Induced Skeletal Muscle Hypertrophy: An Update.

The history, science, and art of wine and the case for health benefits: perspectives of an oenophilic cardiovascular pathologist. (There is a lot about wine itself in parts 1 – 10, and the parts about wine’s effects on health starts at part 11).

Rejuvenation of naturally aged tissues

The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.

Multi‐omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Scientists identify antibodies that can neutralize omicron

An international team of scientists have identified antibodies that neutralize omicron and other SARS-CoV-2 variants. These antibodies target areas of the virus spike protein that remain essentially unchanged as the viruses mutate. By identifying the targets of these “broadly neutralizing” antibodies on the spike protein, it might be possible to design vaccines and antibody treatments…

Scientists identify antibodies that can neutralize omicron

Mitochondrial diseases

Sometimes I work on a case with a rare disease. In one year, I probably come across 5-8 rare diseases, which of course I have to look up because, well, what the hell is this?

One kind of disease that scare me are mitochondrial diseases. These are a group of conditions that are caused by genetic mutations in the mitochondrial DNA that make the mitochondria work abnormally. And if you remember anything about high school biology, mitochondrial are the “powerhouses” of the cell — they produce energy for us to use. So one can imagine that if you have something wrong with your power source, you can’t carry out normal functioning. Also, mitochondrial DNA are only carried in the egg cells, so only mothers can pass this down to their children. Sperm cells don’t carry and therefore don’t contribute mitochondria to the next generation.

It’s crazy how such a small thing can generally f*&k up a life. The US Health & Human Services National Institutes of Health website lists common signs and symptoms such as: poor growth, loss of muscle coordination, muscle weakness, seizures, autism, problems with vision and/or hearing, developmental delay, heart/liver/kidney disease, gastrointestinal disorders, dementia, to name some. You can see what mitochondrial diseases affect in this list of free text research articles at PubMed (I don’t have any institutional access, so I look for free text articles). Then I thought about prenatal testing, and found an article that discusses this, a more recent 2021 article of a study in Japan, and recent (as of 2017) advances in mitochondrial diseases. This article from 2020 is about rare genetic diseases in general, and diagnosing them. If there’s anything I’ve learned from skimming through these articles, it’s that there’s still so much we don’t know. Yet.

OMG, Omicron

Research is what I’m doing when I don’t know what I’m doing.

Wernher von Braun

For the past year and a half, if anyone wanted, they could look to see how science is being done just by looking up research on the SARS-CoV-2 virus. If pandemics were a reality show… Now season 3 is upon us, cursing us with another variant. Like the beginning of finding out about the SARS-CoV-2 virus and finding out about the Delta variant, science is trying to figure this one out. I know that it’s frustrating that no one knows the answer right away, but one thing people miss about science is that it isn’t about knowing everything, but it’s about finding things out. And in order to find things out, we need time. However, in a pandemic, time is an enemy. What some people get wrong is that this is confused with “science is the enemy” or “those other people are the enemy” or “this country is the enemy”. Let’s skip the philosophical part and say that basically, we’re afraid of the unknown, especially if the unknown can maim/kill us.

Although science is more about questions than answers, it can and does generate light that we can shine on the unknown. For example, every Mars rover. Because of my science background (where I spent an extremely long time trying to figure out which science field I wanted to be in, while taking every science class there was), I can go through research articles and figure out what’s what. Here’s a controversial idea: every person should take a class on how to look up scholarly articles on any topic in high school. (While we’re here, let’s open up a school and call it “School of Hard Knocks”, in which every class is directly applicable to real life, such as How to Do Your Taxes, or 50 Cheap, Simple, and Healthy Meals). Anyway, for an average person without a science background (which I also once was, in the early 2000s), what sources are there for just plain facts and neutral ground?

So far, here is the general answer:

I’m happy to see that BBC is in the center, because a long time ago, someone told me that if I wanted to find something neutral, a good point of view to consider would be from people outside of the country. I mean, how good are we at being objective about the aquariums we’re swimming in? And I’m also happy to see Reuters next to BBC. What was interesting was that I had thought The Economist was more right leaning than it was. Finally, it’s nice to know others I haven’t thought of, like Associated Press, to add to my bookmarks.

So what about Omicron? Do we need a booster shot for that? How bad is it, compared to what’s happened already? The answer is, We don’t know… yet.

Now, once again, the world is watching as researchers work nights and weekends to learn what a new variant has in store for humanity. Is Omicron more infectious? More deadly? Is it better at reinfecting recovered people? How well does it evade vaccine-induced immunity? And where did it come from? Finding out will take time, warns Jeremy Farrar, head of the Wellcome Trust: “I’m afraid patience is crucial.”

‘Patience is crucial’: Why we won’t know for weeks how dangerous Omicron is

Talking about sources wasn’t random. I liked this article for its readability, its short length, its international tidbits, and that it shares knowledge (PCR, GISAID database, structural biology mapping) without sensationalizing or politicizing anything. In this day and age, it’s like gold.

Can you be re-infected with the novel coronavirus? A case study.

“An 82-year-old male with a history of advanced Parkinson’s disease, insulin-dependent diabetes, chronic kidney disease, and hypertension presented to the emergency department (ED) in early-April 2020 with one week of fever and shortness of breath. He was hemodynamically stable, but tachypneic, hypoxic to 89% on six liters of oxygen via nasal cannula, and febrile to 100.4 °F. Chest x-ray revealed peripheral and basilar patchy opacities concerning for COVID-19 (Fig. 1A). His respiratory status declined in the ED, and he was intubated for hypoxemic respiratory failure and admitted to the intensive care unit (ICU). An RT-PCR for SARS-CoV-2 sent from the ED resulted as positive. He remained intubated in the ICU for 28 days at which point he was successfully extubated and transferred to the medicine floor. He demonstrated clinical and radiographical improvement (Fig. 1B), and in early May 2020 two subsequent RT-PCRs for SARS-CoV-2 sent 24 h apart resulted as negative. On hospital day 39, he was discharged to a rehabilitation facility breathing comfortably on room air.

Ten days post-discharge (48 days after first presentation), he re-presented to the ED with fever and hypoxia. On arrival he was tachypneic, hypotensive to 70/40 mmHg, and tachycardic to 110 beats/min, with a temperature of 99.9 °F and oxygen saturations of 83% on room air which improved to 96% on eight liters via Oxymizer®. Chest x-ray (Fig. 2A) and computed tomography (CT) scan (Fig. 2B) demonstrated bilateral ground glass opacities again concerning for COVID-19, as well as unilateral focal consolidations concerning for bacterial pneumonia. RT-PCR for SARS-CoV-2 sent from the ED again resulted as positive.”

Was this reinfection? Alternate considerations include the patient shedding virus for a longer period or inaccurate testing.

Genetic material from viruses can stay in a host longer even after live virus has been cleared and after symptoms have resolved. Also, how much virus is shed can depend on how sick the patient was.

According to the article, testing can be inaccurate and imprecise, with test sensitivities of 66% to 80%, depending on what instrument is used. Some tests are sensitive to “multiple different gene targets, some of which are very specific to SARS-CoV-2 infection, and some of which are quite sensitive to detection but may be common among many or all SARS-like coronaviruses.”

However, for this case study, “For our patient, while his RT-PCR on re-presentation was in fact positive, the cycle threshold required for detection was relatively high suggesting a low viral load. This could be explained by either prolonged low-level viral shedding, or inadequacy of the submitted sample. Additionally, at the time of representation and repeat positive testing, further assessment of his results revealed that while the gene assessed which was very sensitive for infection but common among all SARS-coronaviruses was detected, the gene assessed which was specific to SARS-CoV-2 was not identified.”

In conclusion, “There is large variability between instruments used for SARS-CoV-2 RT-PCR testing, and many of these results are largely open to interpretation. As in our case, interpreting cycle thresholds and understanding more about the targets of a particular instrument used for SARS-CoV-2 RT-PCR can be crucial for clinicians assessing for the possibility of true reinfection in their patients.”

Duggan NM, Ludy SM, Shannon BC, Reisner AT, Wilcox SR. A case report of possible novel coronavirus 2019 reinfection [published online ahead of print, 2020 Jul 4]. Am J Emerg Med. 2020;S0735-6757(20)30583-0. doi:10.1016/j.ajem.2020.06.079

Interesting COVID 19 Research

“The most characteristic symptom of patients with COVID-19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID-19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways.”

— Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92(6):552-555. doi:10.1002/jmv.25728.

“A 93-year-old woman was admitted with a 10-day history of cough and prostration. Thoracic computed tomography revealed extensive ground-glass opacities in both the lungs. The polymerase chain reaction test of sputum for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was positive. She was treated with antiviral agents and steroid pulse therapy. However, her oxygen saturation gradually declined, and she died 10 days after hospitalization. The most important autopsy finding was fuzzily segmented diffuse alveolar damage (DAD) that expanded from the subpleural to the medial area. No remarkable changes were observed in organs other than the lungs. Therefore, pneumocytes were suggested as the primary target for SARS-CoV-2, which might explain why coronavirus infectious disease-19 is a serious condition. Thus, early treatment is essential to prevent viral replication from reaching a level that triggers DAD.”

— Okudela K, Hayashi H, Yoshimura Y, et al. A Japanese case of COVID-19: An autopsy report [published online ahead of print, 2020 Aug 13]. Pathol Int. 2020;10.1111/pin.13002. doi:10.1111/pin.13002.

“A relatively high mortality of severe coronavirus disease 2019 (COVID-19) is worrying, and the application of heparin in COVID-19 has been recommended by some expert consensus because of the risk of disseminated intravascular coagulation and venous thromboembolism. However, its efficacy remains to be validated.

“Anticoagulant therapy mainly with low molecular weight heparin appears to be associated with better prognosis in severe COVID-19 patients meeting SIC criteria or with markedly elevated D-dimer.”

— Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. doi:10.1111/jth.14817.