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Cell hacks

Since approximately 2000, scientists have been finding ways to build "biocomputers" and use them to diagnose and treat disease, to produce biofuels and pharmaceuticals, and to address environmental damage (Lu and Purcell 2016).1 In this new field of synthetic biology, researchers are building biological tools that have computing capacities: basic logical (AND, OR, etc) operations, if/then tests, and digital memory. With the right biological inputs, these systems synbio imagegenerate predictable outcomes. These techniques follow from, and surpass, those of genetic engineering.

Biocomputing systems are designed to work with the natural information-processing mechanisms of DNA transcription and translation in cells, essentially running their own programs on biological wetware. Initial advances included a 1-bit digital memory, a rudimentary oscillator, and a "Goldilocks" circuit where a cell would light up only if the concentration of a compound was in a certain range. Biocomputing circuits have been designed to perform basic arithmetic operations such as addition and subtraction, evaluate Boolean operators (eg, AND, OR, XOR), compute ratios and logarithms, convert 2-bit digital signals to analog protein levels, and record and transmit on/off states for logic gates from the parent cell to its children (ie, memory). Many of these are described in detail in the earlier (2004 ) review in Scientific American, the more current review cited above,1 and more recently in Purcell and Lu's review.

Sensors, logic operators, and memory components are being combined into genetic circuits for some pretty interesting applications. For example, a diagnostic application developed at MIT sends a bacterial spy (Bacteroides thetaiotaomicron, a common human gut bacteria) into the mouse gut, where its biocomputing circuits are triggered if it encounters certain disease biomarkers. This leads to the production of luciferase, which can be detected on excretion. This type of system could be used to diagnose inflammatory bowel disease (IBD) or gastrointestinal cancer. (To download the full article, click here.)

A therapeutic application by Xie and colleagues forces a cell to self-destruct if it contains a specific cancerous signature. The presence of 6 different microRNA markers uniquely identifies HeLa cervical cancer cells (3 markers are present at higher than usual concentration and 3 at lower than usual concentration). This system is designed to trigger production of a protein that directs the cell to commit suicide if and only if the 6 types of microRNA are present in the specified high/low pattern.

Compared with conventional computing, biological "computing" has some distinct differences that pose challenges:

• It's slow. No gigahertz speeds here. Biological processes can take hours.
• It's noisy (especially in analog systems). Communication between different parts of the system is "wireless" and not synchronized by any clock.
• It's somewhat unpredictable. We don't know everything about cell behavior. Models are only as good as our knowledge.

As researchers forge ahead exploring this brave-new-world terrain, scholars and advisors at the Synthetic Biology Project, an initiative of the Science and Technology Innovation Program of the Woodrow Wilson International Center for Scholars debate the ethics of this new direction. See their 2009 presentation for an overview.

1 Lu TK, Purcell O. Machine life. Scientific American, April 2016;59-63.

Blogger: Ginny Fleming, Founder, Lucidize Medical & Scientific Editing. Chief capacities: medical, scientific, and technical writing and editing.

 

Finalizing your technical document: A clean, well-lighted place

With a long technical document such as a research paper or technical report, I've found it's impossible to read through the document once and evaluate all structural, content, and formatting isseditpass graphicues at the same time. Using a checklist can be useful. It helps you look at each aspect — the structure, the content, and the formatting — in a systematic way. In the checklist below, some items assume the standard journal article structure (abstract, introduction, methods, results, conclusions, references) for a research study, but they can be adapted to other structures, such as a review article or white paper.

The whole idea is to remove any barriers to understanding between your readers and your document: Think of a solidly built structure, a house with good bones, clean, well-organized, nothing out of place. No visual obstructions. Clear windows, lots of sunlight. Your text, tables, and figures are lucid and easy to follow, with no verbal obstructions or areas of confusion. Nothing distracts your readers or keeps them from understanding your content. That gets you published and gets your findings out to your audience.

Hints:

  • Make a quick separate pass through the document for each checklist item.
  • Try to view the document with fresh eyes (or enlist someone to do this for you).

 

Technical Editing Checklist

Organization/structure review
• Does the document have the appropriate sections for its purpose?
• Are the subsections nested properly?
• Is material duplicated in more than one section? (not a good idea, except in the abstract)
• Is ordering consistent through the document? (eg, same ordering of endpoints in methods and results sections)

Substantive review
• Is the purpose/objective of the study/report clearly stated?
• Do the conclusions address whether you met the objective?
• Does the abstract include a brief description of the study objective, study design, results, and conclusions?
• Does the introduction give a clear picture of how your study is related to past studies and why it is being conducted?
• Are references included for all statements related to published findings?
• Does the methods section describe sample size, enrollment criteria (if applicable), material preparations (if applicable), a detailed description of the study design, measurement parameters and endpoints, and statistical analyses?
• Are the results presented logically (eg, from the most important to least important, or chronologically)?
• Do the results include specific wording to indicate the statistical test performed?
• Are tables warranted to present the data? Using a table will often improve text readability and will always highlight the findings.
• Are figures warranted to illustrate the data? Using a figure will make the findings more easy to grasp at a glance and will always highlight the findings.
• Are the conclusions clearly supported by the results?
• If any data are cited to support the conclusion, have they been presented in the results section? Do not introduce any new findings in the conclusions section.
• Have you explained any shortcomings of the study?
• Consistency cross-checks:

  • Abstract vs. each subsequent section
  • Methods vs. results (results for each stated endpoint/analysis, presented in same order)
  • Results vs. conclusions (conclusions follow from results, presented in same order)


Editorial review
• Read through the document, preferably aloud, and correct the following:

  • Word usage that could be interpreted in more than one way (this warrants a blogpost of its own!) or that is grammatically incorrect
  • Run-on sentences (if you have to track backward to unravel the meaning, it's too long)
  • Run-on paragraphs (can material be chunked into shorter paragraphs of 3-5 sentences?)
  • Material that's in the wrong section (eg, repeating methods info in results section)
  • Too much/too little detail in the abstract
  • Inconsistent terminology

• Do section headings reflect section content? Are they consistent?
• Is section numbering (if applicable) done correctly?
• Do all subjects/verbs agree (singular vs. plural form)?
• Is verb tense consistent and correct through the document?
• Are all style conventions followed (eg, numbers, spacing, punctuation, abbreviations, capitalization)?
• Is spelling correct?
• Is grammar correct?
• Are acronyms defined only on first usage in the abstract and again on first mention in the body of the document?
• Is the table of contents (if applicable) up to date and correctly formatted?
• Are all internal cross-references correct and working? These could include links to a table, figure, appendix, or another numbered section of the document.
• Are figures and tables numbered in the order of citation? If in-line with text, are they close to their referencing text?
• Do figure and table titles reflect content? Are they consistent?
• Are all in-text reference citations in consistent format and present in the reference list (if applicable)?
• Do reference citation links work (if applicable)?
• Does the reference list contain all of the referenced publications in the correct order?
• Are page headers and footers set up correctly?

Formatting review
• Is all text in the appropriate style (eg, font type and size), and is the text formatting consistent throughout the document?
• Is pagination done correctly with no undesired large empty spaces and no blank pages? Pay particular attention to tables, figures, or lists breaking across pages.

For a fascinating exploration of the benefits of checklists in many domains, check out Atul Gawande's "The Checklist Manifesto".

Blogger: Ginny Fleming, Founder, Lucidize Medical & Scientific Editing. Chief capacities: medical, scientific, and technical writing and editing.

Survival of the fattest

What happens in our bodies after weight loss? It takes a lot of effort to lose weight. Recent estimates show that 52% of Americans are trying to lose weight, and an additional 29% are trying to maintain weight loss. Up to one-third of lost pounds are regained in the first year, and as few as 6% of people maintain 5% weight loss after 6 years. Why is it such a hard task, and what do successful losers do to avoid regaining lost pounds?alternative image for after weight loss

Overall, the obesity picture is pretty grim: As of 2011-2012, the majority (69%) of adults in the US were either obese (BMI >30%; 35%) or overweight (BMI 25-30%; 34%). 21% of adolescents were obese, 18% of children ages 6-11, and 8% of children ages 2-5. The prevalence of adult obesity in the US has been increasing steadily since 1980, when it was 15%. Obesity rates have more than doubled in children and tripled in adolescents in the last 30 years. Poor diet/physical inactivity is the 2nd highest cause of death after tobacco use, accounting for approximately 365,000 US deaths in 2000. Total health care costs related to obesity and comorbidities were estimated to be 25% to 44% greater for obese individuals than for their normal-weight counterparts. Thus, the USDA advisory committee on dietary guidelines (2010) proclaimed obesity to be this century's most serious public health threat.

Several factors seem to thwart sustained weight loss and promote recidivism: First, the body is hardwired to maintain weight through complex hormonal feedback loops. Second, hedonic urges in some individuals can be hard to resist. Not to mention that we live in a cultural environment of sedentary lifestyles with high-fat, calorie-dense foods available everywhere.

Let's back up and talk about what happens when you lose weight. Adipose tissue is made up of adipocytes that store energy as fat. An average human adult has 30 billion adipocytes, which altogether weigh about 30 lbs. When weight is gained, fat cells increase in size about 4-fold before dividing to increase the total number of fat cells. When weight is lost, fat cells shrink but the number of fat cells never decreases. People with an excess of fat cells have a harder time losing weight and keeping it off than those with just enlarged fat cells.

Leptin, ghrelin, and other hormones act together to promote energy homeostasis and keep the weight at its set point. Leptin ("the satiety hormone") is secreted by adipocytes, circulates in the blood, and crosses the blood-brain barrier (BBB) to inhibit hunger. Acting in opposition to leptin is ghrelin ("the hunger hormone"), a peptide hormone secreted when the stomach is empty. Ghrelin crosses the BBB and acts on brain receptors to regulate appetite. When the stomach is stretched after eating, ghrelin production stops. Ghrelin levels decrease when sleep is increased; they increase with age.

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A chocolate bar a day keeps the cardiologist away

Chocolate is good for you? What is this, Sleeper? Strangely enough, this addictive treat, loaded with fat and sugar, does seem to be showing consistent, positive effects on cardiovascular health.

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Chocolate is made with cocoa, which is processed from the seeds of a cacao tree (cocoa beans). Cacao has been cultivated for at least 3 millennia in Mesoamerica. Western Africa produces most of the cocoa today, 40% from Ivory Coast. Once the cacao seeds are fermented, dried, and roasted, the hulls are removed, and the remaining cocoa liquor is pressed to separate the cocoa butter from the solids, which are ground to form cocoa powder.

Cocoa has been studied for its many effects on the human body, with particular interest in cardiovascular and cognitive effects. In the cardiovascular arena, cocoa may have antihypertensive, anti-inflammatory, anti-atherogenic, and anti-thrombotic effects. These effects are thought to be due to flavonoids, a group of polyphenolic compounds found ubiquitously in plants. High amounts are found in parsley, onions, berries, teas, bananas, citrus fruits, Ginkgo biloba, red wine, and dark chocolate. Flavonoids are antioxidants that may suppress oxidation of low-density lipoproteins and may reduce risk of cardiovascular disease including stroke. They have also demonstrated anti-allergic, antimicrobial, anti-cancer, and anti-diarrheal activities in vitro.

In cocoa, the flavonoid subcategory thought to be responsible for the antioxidant activity is flavanols, specifically the monomer catechin and its stereoisomer epicatechin. Despite the fact that most of these compounds are destroyed in cocoa processing, chocolate still contains a substantial amount at 460 to 610 mg/kg. Green and black teas and beans can also be quite high in flavanols. Red wine, and fruits such as apricots, cherries, grapes, blackberries, peaches, and apples are additional good sources.

The first inkling that cocoa might have health benefits came from the Kuna people who live on the San Blas islands in Panama. Every day they consume large quantities of a cocoa beverage made from locally grown cacao. An observational study showed that deaths due to cardiovascular causes, cancer, and diabetes mellitus occurred much less frequently in the Kuna compared with people living on the mainland. Cardiovascular events leading to mortality were considerably fewer (8.28 vs. 119 per 100,000). Cancer events were also fewer (3.68 vs. 74.7 per 10,000), as were deaths due to diabetes mellitus (3.68 vs. 24.4 per 10,000). The data were consistent annually over a 4-year period for ischemic heart disease, cancer, stroke, and diabetes. These 2 populations differ in many aspects, not just cocoa consumption, so the actual cause(s) of the differences reported could not be confirmed.

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