Overcoming the "me" goals

I am happy to report that this past week I was off duties and able to recover from the frantic and meaningless activities at work. At least four hours a day I did work on a job assignment; however, "working-while-on vacation" is a routine for me.

The time away from the job has given me the chance to redefine (again) my smaller- and bigger-scale goals, learn more about some financial tools, and ruminate on how to align the spiritual with the material.

I hope that you also have had some time around the holidays to ponder about what comes next in your life.

I have also been listening to the podcasts of ChooseFI. I have been reading some of the latest posts of JL Collins and the other FI (financial independence) people (look here).

It is refreshing to learn from a bunch of highly organized, intentional and reflective people how they perceive life and how they prepare for intentional existence. The FI folks truly create the impression of being masters of their lives. They know what their goals are, they know how to get there, they track each step in the journey. 

I have only admiration (and a bit of envy) for these guys. In contrast, the only thing I currently know is that I would love to get out of the current job in four years. However, I have no clear idea on what I will do after these four years. And this means that my journey is not inspired. The goals and my next life destination should be the driving force that fuels me through the years. As of now, I am unsure that I can make it through almost 1500 workdays (that's right, I count weekends too, and with a good reason)!  

My next assignment is to think what comes after the 1500 days, so that I could align the material needs with my spiritual aspirations. The default would be to bum around for some time after I have secured the minimum "survival" income, and then my inspiration might come ... All I know is that my dream is not what is described at the beginning of this podcast:

I would rather visit the local library every week, have a modest and cozy home, and maybe have a garden. And maybe if I am not working even during my "vacation time", I would be able to find myself again and rediscover what truly motivates me? 

I just found the blog of the Wealthy Accountant, and interestingly, this post by him discusses the need for a simple goal when one strives for early retirement.  I still have to work on my own goal by externalizing it, i.e., by making it more about others than myself.  Being cozy and having enough time for books and gardening is great, but it is awfully egotistical.What is your goal?

Creatine And Resistance Exercise For Older Individuals

Creatine supplementation has been shown to be helpful in building muscle mass and strength in older individuals undergoing resistance training; however, the mechanisms of action have not been definitively established.  Abstract:

The loss of muscle mass and strength with aging results in significant functional impairment. Creatine supplementation has been used in combination with resistance training as a strategy for increasing lean tissue mass and muscle strength in older adults, but results across studies are equivocal. We conducted a systematic review and meta-analysis of randomized controlled trials of creatine supplementation during resistance training in older adults with lean tissue mass, chest press strength, and leg press strength as outcomes by searching PubMed and SPORTDiscus databases. Twenty-two studies were included in our meta-analysis with 721 participants (both men and women; with a mean age of 57-70 years across studies) randomized to creatine supplementation or placebo during resistance training 2-3 days/week for 7-52 weeks. Creatine supplementation resulted in greater increases in lean tissue mass (mean difference =1.37 kg [95% CI =0.97-1.76]; p<0.00001), chest press strength (standardized mean difference [SMD] =0.35 [0.16-0.53]; p=0.0002), and leg press strength (SMD =0.24 [0.05-0.43]; p=0.01). A number of mechanisms exist by which creatine may increase lean tissue mass and muscular strength. These are included in a narrative review in the discussion section of this article. In summary, creatine supplementation increases lean tissue mass and upper and lower body muscular strength during resistance training of older adults, but potential mechanisms by which creatine exerts these positive effects have yet to be evaluated extensively.

High-Fidelity CRISPR

A more accurate “high-fidelity” CRISPR system will enable more precise editing of genomes and opens up the hope for optimized gene therapy approaches for human disease, particularly genetic diseases.  Abstract:

The RNA-guided CRISPR-Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing1-4. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity are unknown5-9. Using single-molecule Förster resonance energy transfer (smFRET) experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state10 when bound to mismatched targets. We find that a non-catalytic domain within Cas9, REC3, recognizes target complementarity and governs the HNH nuclease to regulate overall catalytic competence. Exploiting this observation, we designed a new hyper-accurate Cas9 variant (HypaCas9) that demonstrates high genome-wide specificity without compromising on-target activity in human cells. These results offer a more comprehensive model to rationalize and modify the balance between target recognition and nuclease activation for precision genome editing.

Gene Therapy For Deafness

Here we see a CRISPR-based system for gene therapy against a form of hereditary deafness, tested fairly successfully in the Beethoven mouse model, with “substantially reduced progressive hearing loss” and better survival of ear cells and a lower auditory response threshold. Gene therapy progress marches onward.  Abstract:

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Life is an experiment

Yep, it is best when life is a series of experiments, and I hope that you are planning and/or implementing your next experiment right now. Remember one of my last posts about searching for meaning? Well, experiments are the approach of this search.

My experiment today is modest and not too impressive: I  will prepare a Christmas Eve dinner that is VEGAN. That is right, according to my ethnic background, on Christmas Eve, we do not eat any meat or any animal products.

So, I am planning on: red peppers stuffed with spicy chickpeas, roasted walnuts, potato-onion salad, homemade high-fiber bread, and baked apples. Here are the details:

1. Stuffed peppers. The peppers are coming roasted and peeled from a jar. The chickpeas are from cans, I already made them crispy and spicy in a pan with olive oil, garlic, cayenne pepper, paprika, salt, mint, and winter savory. I crushed them a bit. (If the bean mixture is too dry, add a bit of salsa or cut tomatoes.) Later on, I will stuff the peppers and bake these quickly (just to warm up) in a pan with olive oil.

2. Potato salad. I will boil some red potatoes (cleaned and cut) with the skin and mix them with one sweet onion. The onion will be cut thinly, crushed with salt and covered in olive oil and apple cider vinegar before the potatoes are ready.

3. Spicy walnuts. I will mix the walnuts with spicy Buffalo wings sauce and bake. The sauce sticks to the nuts better if it is thicken with starch or arrowroot powder.

4. Bread. I will use my recipe for fried dough. In this case; however, I will divide the dough into fist-sized balls and baked them on an oiled cookie sheet to have individual breads for everyone. The breads are usually baked at 350 F for 35-40 minutes.

5. Baked apples. I will cut these in two halves, remove the core with the seeds with a little teaspoon, then arrange them in a spayed pan, sprinkle with cinnamon, and bake at 400F. I usually cover the apples with foil for most of the baking time. Depending upon the type of apples, baking time differs, so I would recommend to try for readiness by piercing an apple with a fork. If the fork goes in easily, the apple is ready.

Collaboration In Science Across Disciplines

By J.J. at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=671715

A statement in favor of cross-disciplinary scientific collaboration is here (abstract below).  Based on my own experiences, and anecdotal evidence collaboration across disciplines may be easier than within a discipline, because of the competition and personal hostilities that exist between scientists within a discipline.  On the other hand, cross-disciplinary collaboration requires open-mindedness, a trait that many scientists these days surprisingly do not have.

"Science" is under increasing amounts of scrutiny. Concerns about reproducibility, reduced institutional support, and intensified competition has been highlighted in recent years, but segregated science endangers scientific discovery above all. Segregated science can be interdisciplinary (biology vs psychology) or interdisciplinary (behaviorism vs cognitive psychology). The advancement of science and public knowledge depends on the unification of all disciplines to better understand the phenomena scientists study. We suggest that engendering collaborations across scientific disciplines produces better-designed research and appropriate interpretations, and increases career-long success. I am not a cognitive psychologist, behaviorist, or biologist because I am a neuroscientist.

Salt, Microbiota, and High Blood Pressure

A high salt diet can alter gut microbiota, which in turn induces certain immune cells that can contribute to autoimmunity leading to, among other problems, high blood pressure.  This finding provides more evidence foe the link between diet, gut microbiota, and altered human health, and also demonstrates a novel mechanism whereby a high salt diet contributed to hypertension.  Abstract:

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Marcus Aurelius and an Oat Banana Baked French Toast

Hello, everyone!

I have two good things to share today.

The first one is a great lecture on Marcus Aurelius, and the second is a recipe for an oat banana baked toast that I found on Pinterest.

I listened to the “Best Lecture on Stoicism" yesterday. I have previously liked the brief video on stoicism, STOICISM - MEDITATIONS BY MARCUS AURELIUS ANIMATED BOOK REVIEW by FightMediocrity, so I decided to watch more on the Roman emperor. I was not disappointed. The lecture was dynamic, well presented, without a whiff of stale academics. And of course, it was relevant, especially today, when we have a crisis in leadership at all levels. There were several highlights in the talk; for example, one was the thought of why it is pointless to be mean to each other – after all we all will die. But as it is with any great piece of art (or in this case, a great philosophy), I am sure that when you listen to the lecture, you will find your own “best moments” to appreciate and think about.
 

Oat Banana Baked French Toast: added sugar-free version

So much for the food for the soul. Now about the food that keeps the body engine going. I found the recipe for an oat-banana baked French toast on Pinterest; however, it was a bit decadent for my taste (with nut butter, maple syrup, etc.). So, I skipped these and instead of any bread, I used double fiber bread, added two eggs for protein and five tablespoons of cream of wheat (I need the iron). I also scaled up the recipe to six servings to be prepared in a single baking pan. By the way, the author of the original recipe is Amanda @ Running with Spoons. Thank you, Amanda! Here is my modified version:

Ingredients (for six servings):
· 3 bananas, mashed
· 1.5 (or more) cups unsweetened almond milk (found in any supermarket, even ours!)
· 2 Tbsp ground cinnamon
· 2 Tbsp vanilla
· 6 slices of Double Fiber bread, cubed
· 1.5 cups oats
· 2 eggs
· 5 Tbsp cream of wheat (optional)

Directions:
1. Preheat oven to 375F, prepare a pan with a non-stick spray.
2. Mix the eggs, milk, mashed bananas, and cream of wheat. Add the cinnamon and vanilla. Soak the bread cubes and oats in the mixture, stir.
3. Transfer the mixture to the pan.
4. Bake for 45 minutes. I baked mine in a toaster-oven and used a clean knife to test for readiness (if the knife comes out clean, the toast is ready).

The verdict?  The “toast” was edible, with a very mild taste; however, if you are not used to low- or no-sugar food, it would take some adjustment of your palate. If you have a sweet tooth, I suggest to start the recipe with a tablespoon or two of maple syrup, and then wean yourself to no additional sugar (other than the sugar from the banana). You could add a few walnuts and raisins, which would make the taste more interesting. Overall, it is a thumbs-up recipe and I am planning on perfecting it further this holiday season!

Looping DNA

The formation of DNA loops is an integral mechanism in the control of gene expression, bringing various control regions of DNA, and their associated transcriptional factors and chromatin remodeling complexes, in proximity – even across long distances – to affect modulation of expression of the relevant genes.  The ability to control such looping would be a new tool to target and modify specific gene expression for experimental and therapeutic benefit.  A modification of the CRISPR system shows promise to effect such novel control mechanisms.  Abstract:

DNA looping is a ubiquitous and critical feature of gene regulation. Although DNA looping can be efficiently detected, tools to readily manipulate DNA looping are limited. Here we develop CRISPR-based DNA looping reagents for creation of programmable DNA loops. Cleavage-defective Cas9 proteins of different specificity are linked by heterodimerization or translational fusion to create bivalent complexes able to link two separate DNA regions. After model-directed optimization, the reagents are validated using a quantitative DNA looping assay in E. coli. Looping efficiency is ~15% for a 4.7 kb loop, but is significantly improved by loop multiplexing with additional guides. Bivalent dCas9 complexes are also used to activate endogenous norVW genes by rewiring chromosomal DNA to bring distal enhancer elements to the gene promoters. Such reagents should allow manipulation of DNA looping in a variety of cell types, aiding understanding of endogenous loops and enabling creation of new regulatory connections.

Circular RNA, Type 2 Diabetes, And Depression

Production of circular RNA.  By Helixitta - Own work, created for Biology week #3, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=56444195

There is a link between type 2 diabetes and depression; expression of circular RNAs (unusual RNAs that are in circular rather than normal linear form and are therefore more stable and may affect gene expression differently) may be mechanistically linked to this association. Abstract:

Type 2 diabetes mellitus (T2DM) is closely related to depression; however, the exact molecular mechanisms of this association are unknown. Here, we investigated whether circular RNAs (circRNAs) in the blood are related to the occurrence of depression in patients with T2DM. Fourteen patients with T2DM and depressive symptoms, as assessed by the Self-Rating Depression Scale, were included in this study. Cutoff points of 44 (total coarse points) and 55 (standard score) were used to define depression. The Patient Health Questionnaire 9 was used for common mental disorders, and a score of 5 or more the cutoff for depression. Microarray assays and quantitative real-time reverse transcription polymerase chain reaction showed that 183 hsa-circRNAs were significantly upregulated, whereas 64 were downregulated in the T2DM with depression group (p < 0.05) compared with that in the T2DM group. Differentially expressed hsa-circRNAs could interact with microRNAs to target mRNA expression. KEGG pathway analysis predicted that upregulation of hsa-circRNA_003251, hsa-circRNA_015115, hsa-circRNA_100918, and hsa_circRNA_001520 may participate in the thyroid hormone, Wnt, ErbB, and mitogen-activated protein kinase signalling pathways. We speculate that differentially expressed hsa-circRNAs could help us to clarify the pathogenesis of depression in patients with T2DM and could represent novel molecular targets for clinical diagnosis and therapy.

A Different Kind Of Poker

We are being replaced!  Now in poker!  Abstract:

No-limit Texas hold'em is the most popular form of poker. Despite AI successes in perfect-information games, the private information and massive game tree have made no-limit poker difficult to tackle. We present Libratus, an AI that, in a 120,000-hand competition, defeated four top human specialist professionals in heads-up no-limit Texas hold'em, the leading benchmark and long-standing challenge problem in imperfect-information game solving. Our game-theoretic approach features application-independent techniques: an algorithm for computing a blueprint for the overall strategy, an algorithm that fleshes out the details of the strategy for subgames that are reached during play, and a self-improver algorithm that fixes potential weaknesses that opponents have identified in the blueprint strategy.

Therapeutic Targets For Non-Hodgkin Lymphoma

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11219741

Here is a study looking at deregulated signaling pathways in non-Hodgkin lymphoma patients, with the objective of finding target proteins for therapeutics.  Some targets were identified, and these can serve as targets of future studies to identify therapeutic approaches.  Thus again shows the link between basic science and human disease treatment. Abstract:

Autoantibody profiling with a systems medicine approach can help identify critical dysregulated signaling pathways (SPs) in cancers. In this way, immunoglobulins G (IgG) purified from the serum samples of 92 healthy controls, 10 pre-treated (PR) non-Hodgkin lymphoma (NHL) patients, and 20 NHL patients who underwent chemotherapy (PS) were screened with a phage-displayed random peptide library. Protein-protein interaction networks of the PR and PS groups were analyzed and visualized by Gephi. The results indicated AXIN2, SENP2, TOP2A, FZD6, NLK, HDAC2, HDAC1, and EHMT2, in addition to CAMK2A, PLCG1, PLCG2, GRM5, GRIN2B, GRIN2D, CACNA2D3, and SPTAN1 as hubs in 11 and 7 modules of PR and PS networks, respectively. PR- and PS-specific hubs were evaluated in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. The PR-specific hubs were involved in Wnt SP, signaling by Notch1 in cancer, telomere maintenance, and transcriptional misregulation. In contrast, glutamate receptor SP, Fc receptor-related pathways, growth factors-related SPs, and Wnt SP were statistically significant enriched pathways, based on the pathway analysis of PS hubs. The results revealed that the most PR-specific proteins were associated with events involved in tumor development, while chemotherapy in the PS group was associated with side effects of drugs and/or cancer recurrence. As the findings demonstrated, PR- and PS-specific proteins in this study can be promising therapeutic targets in future studies.

Tribulations by an old hag

Cornelis Bisschop - Old Woman Sleeping

These days I feel old. I feel ancient. People say wisdom comes with age. I am in desperate need of that age-dependent wisdom. Instead of getting wiser and smarter, today I find myself like a child, confused, puzzled, without any idea what I am doing and where I am going.

I was listening to someone rich and famous these days. He was an arrogant swindler who accumulated money in a sketchy way; a guy, who did not produce anything but has millions of dollars. And yet, he said something that I have realized a decade ago – adults do not know what they are doing. When you are a child, you firmly believe that all adults know what they are doing, why they are doing it, and where they are going. In fact, they do not. I do not know where I am going. I constantly struggle and constantly change my mind. I am like a particle that randomly changes its direction. There is no final destination, no final target in my mind. Random thoughts flood my brain and sway me from one extreme to another.

On a daily basis, I sway from fear to indifference. There is not a second of elation or excitement. If I force myself to plan my life ahead, the only plan is to avoid possible disasters that hammer at my brain. These are the disasters that haunt us all – the poor health ahead, the lack of money, the loneliness, the sense of not belonging, the belief that at end of our life we will regret everything … There are never positive thoughts of achieving, creating, establishing something new and useful.

This introspective state of criticism installs itself only at times when I take a few days off of work. Otherwise, work keeps me utterly busy with excruciatingly stupid, silly, and useless activities. At the end of the workday, I am an empty bag, a drab worn-out sack that contains nothing. The only redeeming quality of my job is that it is so time-demanding that I do not have a minute to ponder the fact that I am going nowhere, that I have no purpose, that I do not know what I am doing on the greater scale of life. Otherwise, I am German-level organized and disciplined: I account for every minute of mine, I work on weekends, I maximize every second of my home life. When I do not work for the paycheck, I have the food list in my mind when I do the weekly pilgrimage to the supermarket, I have my little tasks clicking in my mind in a sequential order: (1) clean the rug, (2) take the mop, (3) cut the veggies, (4) start the pot for the soup, etc. I work like the Energizer Bunny on batteries that never give up.

Only in the evenings, for one or two hours, I allow my mind to drift away from the tracks of work and obligations. This is usually the time when I walk and listen to a few podcasts and interviews. I listen to people ranting about their passions and strives, about their accomplishments, life lessons and life hacks. I also read a little before closing my eyes with the hope for oblivion and sleep.

Sometimes it is a book that reboots my mind and then I realize how deprived I am. Not of food, warmth, or company. I am deprived of emotions and big ideas. I am deprived of meaning. I desperately look at others to fill in the void, without realizing that the only one to fill in the void is me.

The book that rebooted my brain out of the vicious work-home-work cycle, and prodded me write this post was Chocolat by Joanne Harris. I got the book last week, during one of my regular raids in the local library. In the library, I never pick books I have previously decided to look for. I usually float by the shelves, throw a glance at the back cover, and take a second or two to decide on whether the book is worth my time or not.

It was only when I came home and opened the book, that I realized that I have seen the movie based on the published work. 

The book is about a wanderer and her daughter, about the time when they finally have stopped their world journey and are in a small French village. The mother and child have opened a place that offers chocolate in all its seductive shapes and forms. Along with the chocolate comes love, generosity and search for meaning. It is a book about a strong woman, who like all of us, is in search.

And this is a comforting thought: life is a constant search, whether we like it or not. There is no finite state of contentment and achievement. A static state like this would be the kiss of death. Till our last moment we need to search. The fact that I do not know where I am going and what I am doing might be a blessing in disguise.

So, this book of chocolate seduction, colors, scents, geraniums, generosity, love, nourishing food, imagination, folklore, superstition, everyday life and death made me realize that the search for meaning is the meaning of life.

I am still hungrily devouring page here and there. After I finish the first reading of Chocolat, I will read it again; the second time I will slowly take in each word and internalize it.