Cartilage Repair, Cell Signaling, And Osteoarthritis

Cartilage repair, aging, and osteoarthritis; new findings described here.  Cell signaling pathways are involved; modulating these pathways may be part of new, optimized treatments for this disease.  

Ageing processes play a major contributing role for the development of Osteoarthritis (OA). This prototypic degenerative condition of ageing is the most common form of arthritis and is accompanied by a general decline, chronic pain and mobility deficits. The disease is primarily characterized by articular cartilage degradation, followed by subchondral bone thickening, osteophyte formation, synovial inflammation and joint degeneration. In the early stages, osteoarthritic chondrocytes undergo phenotypic changes that increase cell proliferation and cluster formation and enhance the production of matrix-remodelling enzymes. In fact, chondrocytes exhibit differentiation plasticity and undergo phenotypic changes during the healing process. Current studies are focusing on unravelling whether OA is a consequence of an abnormal wound healing response. Recent investigations suggest that alterations in different proteins, such as TGF-ß/BMPs, NF-Kß, Wnt, and Cx43, or SASP factors involved in signalling pathways in wound healing response, could be directly implicated in the initiation of OA. Several findings suggest that osteoarthritic chondrocytes remain in an immature state expressing stemness-associated cell surface markers. In fact, the efficacy of new disease-modifying OA drugs that promote chondrogenic differentiation in animal models indicates that this may be a drug-sensible state. In this review, we highlight the current knowledge regarding cellular plasticity in chondrocytes and OA. A better comprehension of the mechanisms involved in these processes may enable us to understand the molecular pathways that promote abnormal repair and cartilage degradation in OA. This understanding would be advantageous in identifying novel targets and designing therapies to promote effective cartilage repair and successful joint ageing by preventing functional limitations and disability.

Against Fibrosis

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8674830

Fibrosis, a disorder characterized by formation of excess connective fibrous tissue, is common in various disease states, including cardiovascular and kidney disease, negative affecting the function of these organs.  A new study suggests that inhibition of interleukin 11 signaling can repress fibrosis formation and can serve as a possible therapy for fibrotic disease.  Abstract:

Fibrosis is a final common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFB1) is the principal pro-fibrotic factor4,5 but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesised that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, we found that Interleukin 11 (IL11) upregulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. IL11 and its receptor (IL11RA) are expressed specifically in fibroblasts where they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il11 injection causes heart and kidney fibrosis and organ failure whereas genetic deletion of Il11ra1 is protective against disease. Thus, inhibition of IL11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These data reveal a central role of IL11 in fibrosis and we propose inhibition of IL11 as a new therapeutic strategy to treat fibrotic diseases.

Cosmic Rays And Cognitive Decline (And A Hypothesis)

By NASA/JPL-Caltech/SwRI - http://photojournal.jpl.nasa.gov/jpeg/PIA16938.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=26429266

Galactic cosmic radiation may prove  a problem for deep-space travel, and a study demonstrates that similar high-intensity radiation in mice caused cognitive decline and changes in gene expression in the hippocampus (a part of the brain whose importance is discussed in the abstract reproduced below).  One wonders if long exposure to the less intense, lower energy cosmic radiation that we are exposed to on the Earth's surface contributes to cognitive decline with age.  Therefore, the hypothesis is that long-term exposure to weaker cosmic radiation may have similar effects to short-term exposure to more intense cosmic radiation.  On the other hand, it may be possible there is a threshold effect and only high energy does the damage.  We may be adapted to deal with lower level radiation on the Earth's surface; however, cognitive decline with old age may not be strongly selected against if it is far enough removed from the reproductive age. In summary it is a hypothesis worth looking into.  Abstract:

Radiation from galactic cosmic rays (GCR) poses a significant health risk for deep-space flight crews. GCR are unique in their extremely high-energy particles. With current spacecraft shielding technology, some of the predominant particles astronauts would be exposed to are 1H + 16O. Radiation has been shown to cause cognitive deficits in mice. The hippocampus plays a key role in memory and cognitive tasks; it receives information from the cortex, undergoes dendritic-dependent processing and then relays information back to the cortex. In this study, we investigated the effects of combined 1H + 16O irradiation on cognition and dendritic structures in the hippocampus of adult male mice three months postirradiation. Six-month-old male C57BL/6 mice were irradiated first with 1H (0.5 Gy, 150 MeV/n) and 1 h later with 16O (0.1 Gy, 600 MeV/n) at the NASA Space Radiation Laboratory (Upton, NY). Three months after irradiation, animals were tested for hippocampus-dependent cognitive performance using the Y-maze. Upon sacrifice, molecular and morphological assessments were performed on hippocampal tissues. During Y-maze testing, the irradiated mice failed to distinguish the novel arm, spending approximately the same amount of time in all three arms during the retention trial relative to sham-treated controls. Irradiated animals also showed changes in expression of glutamate receptor subunits and synaptic density-associated proteins. 1H + 16O radiation compromised dendritic morphology in the cornu ammonis 1 and dentate gyrus within the hippocampus. These data indicate cognitive injuries due to 1H + 16O at three months postirradiation.

More Benefits Of DASH

The DASH diet can reduce depression along with all of its other health benefits.

The popular Dietary Approaches to Stop Hypertension (DASH) diet was created to lower blood pressure, but new research says it can also reduce the risk of depression later in life.

A study, to be presented at the American Academy of Neurology’s 70th Annual Meeting in April, shows that the popular diet -- rich in vegetables, fruit, whole grains, fat-free or low-fat dairy products and very few foods that are high in saturated fats and sugar -- does more than what has been shown in multiple studies: Lowering blood pressure, bad cholesterol (LDL) and body weight.

Keep on eating those Big Macs though!

In all seriousness, people have a choice between healthy and unhealthy eating, and this choice should be reflected in health insurance premiums.

Food Quality Over Quantity

Following up on this post, read this about the same study.

Paying attention to the quality of the food is more effective for weight loss than religiously counting calories, according to a new study.

Researchers at Stanford University found there is no significant difference in weight change between a healthy low-fat diet versus a healthy low-carbohydrate diet.

The 12-month weight loss study of 609 individuals found the tactic of choosing whole, unprocessed foods and not worrying about calories resulted in similar weight loss for people following both diets.

The study also found there is no specific insulin levels associated with the dietary effects of weight loss and no specific gene pattern that affected which diet made an individual lose weight.

Again, the take home points about weight loss: food quality is more important than counting calories, genetic excuses are not justified, and fad diets are not required.

Don’t Blame Your Genes

It’s not your genes, it’s your appetite and eating habits.

But weight loss averaged about 13 pounds over a year, regardless of genes, insulin levels or diet type. Also, some people lost as much as 60 pounds and others gained 15 pounds — more evidence that genetic characteristics and diet type appeared to make no difference.

What seemed to make a difference was healthful eating. Participants on both diets who consumed the fewest processed foods, sugary drinks, unhealthy fats and ate the most vegetables lost the most weight.

The results suggest that "precision medicine is not as important as eating mindfully, getting rid of packaged, processed food" and avoiding unhealthy habits like eating while watching television, said lead author Christopher Gardner.

So, excuses about “it’s my genes” do not justify BMI realities, and fad diets are a waste of time, if key essentials are met: “Participants on both diets who consumed the fewest processed foods, sugary drinks, unhealthy fats and ate the most vegetables lost the most weight."

I for one cut out sugary drinks – including orange juice and other fruit juices – cut back on saturated fats, cut back on foods with lots of added sugar, eat a bit less “packaged food,” while increasing fruits, vegetables, and whole grain as opposed to white.

Priobiotics, Intestinal Integrity, and Health

More evidence for the importance of the proper intestinal bacteria, and possible utility of probiotics. Abstract:

Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major aetiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clinical trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the reduction of gastrointestinal disease symptoms.

Note that disruption of the integrity of the intestinal epithelium (in layman’s terms: lining of the gut) is associated with a wide variety of important diseases, and that probiotics can enhance that integrity and reduce symptoms of gastrointestinal disease. The paper discusses various mechanisms whereby “good bacteria” help fight against “bad bacteria” and in so doing reduce inflammation and help maintain the proper structure of the intestines, hence helping reduce disease. The good bacteria occupy space and use nutrients that otherwise could be exploited by the bad bacteria, the good bacteria can secrete molecules that are toxic to the bad bacteria, and the good bacteria can help stimulate immune responses that target the bad bacteria. One home measure that I and people in my immediate family do is to make sure we eat yogurt with active cultures when we are on antibiotics, and after the antibiotic course is finished, to make sure the proper intestinal bacteria are being replenished as they are being killed, as a side effect, by the antibiotics. The aim is to inhibit colonization of the guy by the bad bacteria, especially once the antibiotic course is finished, by making sure that enough of the “good guys” are present. Of course, consult with your physician before doing this yourself and be aware that some antibiotics should not be taken with dairy products (and of course, be aware if you are lactose intolerant – although many intolerant individuals can tolerate yogurt, or have a dairy allergy). We usually eat yogurt anyway, so doing so in this case is nothing unusual.

Microbiome And Sex-Specific Brain Development

The microbiome can affect microglia development in a sex-specific manner, which has implications for brain development and function.  This occurs in mice, but mouse and human microglia exhibit enough similarities that we can suspect that the same situation holds for humans as well.  This once again demonstrates the profound impacts of microglia, as well as that of sex-specific developmental differences.  Abstract:

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.

Introducing CancerSEEK

A blood test, CancerSEEK, has shown some efficacy in detecting a variety of cancer types, including some for which screening is currently difficult or impossible (although stomach, which is listed by them in that category, can be interrogated by upper GI endoscopy or barium imaging).  Interesting, some data can be obtained from this blood test to actually localize where the tumor is to a small number of anatomic locations for the types of cancer studied.  This is a promising diagnostic tool.  Abstract:

Earlier detection is key to reducing cancer deaths. Here we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1,005 patients with non-metastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69% to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was > 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

Gut Microbiome In FAP

The gut microbiome is known to typically be abnormal in patients with sporadic colorectal cancer (CRC).  A study has now shown that individuals with a form of hereditary CRC have bacterial biofilms containing tumorigenic, cancer-promoting bacterial strains, and exhibit cancer-promoting gene expression due to this bacterial colonization.  Mouse models of CRC exhibit accelerated tumor development when colonized by these strains.  These important findings underscore the importance of the gut bacteria and suggests targets for therapeutic intervention. Abstract:

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.

Western Diet And Inflammation

A Western diet can not only promote cancer in mice, it also causes inflammation, and even after the mice are switched back to their normal diet, myeloid cells show enhanced immune response.  This change seems dependent on the product of the NLRP3 gene.  Thus, the high fat, calorie-dense Western diet can contribute to long-term, pro-inflammatory, negative alterations in the immune system and this likely is relevant for humans as well as mice.

Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed "trained immunity," causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr-/- mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3-/-/Ldlr-/- mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.

Eating more fruits and vegetables may indeed be a good idea.

Broken Heart Syndrome

By J. Heuser JHeuser - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=889151

Takotsubo cardiomyopathy or “broken heart syndrome” is a form of heart disease “precipitated by intense emotional stress.” It has previously been thought to be transient and reversible in nature, but a study has now shown sufferers exhibit long-term heart damage.  It is impossible to avoid intense emotional stress I life, but everyone must try and deal with it as best as they can, and if this disorder happens to them, they will seem to need long-term evaluation by a cardiac specialist. Abstract:

BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined. METHODS: In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy. RESULTS: Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P<0.001; increased VE/VCO2 slope, 31±1 versus 26±1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, ‒16±1.0 versus ‒23±1.5%, P<0.001; global longitudinal strain, ‒17±1 versus ‒20±1%, P=0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/γ-adenosine triphosphate ratio, 1.3±0.1 versus 1.9±0.1, P<0.001). CONCLUSIONS: In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02989454.

Perchance To Dream…But Not When Lifting

Muscle strength in lifting, particularly heavy compound movements, is impaired by lack of sufficient sleep; thus: 

Inadequate sleep impairs maximal muscle strength in compound movements when performed without specific interventions designed to increase motivation. Strategies to assist groups facing inadequate sleep to effectively perform resistance training may include supplementing their motivation by training in groups or ingesting caffeine; or training prior to prolonged periods of wakefulness.

If the situation is unavoidable, then do what you can, but the optimal thing is to just get enough sleep (easier said than done in many cases, I know….).

Soy, Genistein, And Prostate Cancer

The soy isoflavone genistein has a variety of antitumor effects both in cell culture (in vitro) and in animal models (in vivo).  In particular, genistein can have beneficial effects against prostate cancer cells, targeting certain cell signaling pathways as well as targeting certain microRNAs that affect gene expression.  These findings can help explain health benefits of soy as well as identify targets for other therapeutic interventions.  Abstract:

OBJECTIVE:

Genistein is a soy isoflavone that has antitumor activity both in vitro and in vivo. It has been shown that genistein inhibits many type of cancers including prostate cancer (PCa) by regulating several cell signaling pathways and microRNAs (miRNAs). Recent studies suggest that the long non-coding RNAs (lncRNAs) are also involved in many cellular processes. At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa.

METHOD:

Microarray (SurePrint G3 Human GE 8×60K) was used for expression profiling of genistein treated and control PCa cells (PC3 and DU145). Functional assay (cell proliferation, migration, invasion, apoptosis and cell cycle assays) were performed with the PCa cell lines, PC3 and DU145. Both in vitro and in vivo (nude mouse) models were used for growth assays. Luciferase reporter assays were used for binding of miR-34a to HOTAIR.

RESULTS:

LncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells.

CONCLUSIONS:

Our results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is also targeted by tumor suppressor miR-34a. These findings enhance understanding of how genistein regulates lncRNA HOTAIR and miR-34a in PCa.

Inflammation, Immune Cells, And Liver Cancer

Chronic inflammation due to non-alcoholic fatty liver disease alters immune cells, resulting in more cells that produce factors that suppress anti-cancer immunity, therefore increasing the risk for liver cancer.  Note that non-alcoholic fatty liver disease is associated with metabolic syndrome, which is itself associated with being overweight/obese.  An association between poor weight control and liver cancer>  You do the math. Abstract:

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.

Semi-Synthetic Organism Advances

Producing semi-synthetic organisms.  This can lead to organisms designed to digest pollution, produce novel materials and biomedicine, innovative therapies for human injury or disease, and many other uses, as well as giving a better understanding of life processes that can be used to create fully synthetic organisms in the future.  Abstract:

Since at least the last common ancestor of all life on Earth, genetic information has been stored in a four-letter alphabet that is propagated and retrieved by the formation of two base pairs. The central goal of synthetic biology is to create new life forms and functions, and the most general route to this goal is the creation of semi-synthetic organisms whose DNA harbours two additional letters that form a third, unnatural base pair. Previous efforts to generate such semi-synthetic organisms culminated in the creation of a strain of Escherichia coli that, by virtue of a nucleoside triphosphate transporter from Phaeodactylum tricornutum, imports the requisite unnatural triphosphates from its medium and then uses them to replicate a plasmid containing the unnatural base pair dNaM-dTPT3. Although the semi-synthetic organism stores increased information when compared to natural organisms, retrieval of the information requires in vivo transcription of the unnatural base pair into mRNA and tRNA, aminoacylation of the tRNA with a non-canonical amino acid, and efficient participation of the unnatural base pair in decoding at the ribosome. Here we report the in vivo transcription of DNA containing dNaM and dTPT3 into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of natural or non-canonical amino acids into superfolder green fluorescent protein. The results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions.

A Scientific Complaint

As an academic scientific researcher, I have to admit that it is highly annoying when other researchers publish on a topic as if they were the first to discover something and, do not cite your work that had discovered the exact same thing years before.  In fact, in some cases, not only have you published your findings, and then published follow-up extensions of it, but also have published review articles on that discovery and its implications in the field.  And despite all of that, easily accessible on PubMed or easily found in a Google search, others will, many years later, repeat the work and claim it as their own.  That is not only a form of plagiarism, but a waste of time and resources, and further shows the low quality of the editors and, especially the reviewers of that new article who haven’t bothered to look at whether the “new” work had already been done long ago.  

Certainly, there is a place for reproducibility and confirming results, but not presented as a novel discovery, nor published as such.

These things happen more often than you would think; it has happened to me several times already.

Cleft Wnt

Wnt signaling influences cleft lip and cleft palate; abstract:

OBJECTIVE:Nonsyndromic cleft lip with or without cleft palate (NSCL±P) is a common craniofacial anomaly with multifactorial etiology. Evidence suggests that variations in WNT pathway genes contribute to an increased susceptibility to NSCL±P. The aim of this study was to investigate the association of AXIN1, APC, CTNNB1, DVL2, and GSK3β gene variants with NSCL±P in a case-control data set from Brazil.PATIENTS:471 individuals with NSCL±P and 504 unrelated control individuals of Caucasian ethnicity.DESIGN:Twenty single-nucleotide polymorphisms (SNPs) in/nearby AXIN1, APC, CTNNB1, DVL2, and GSK3B genes were genotyped using Taqman chemistry in a Viia7 sequence detection instrument. Genotype, allele, and haplotype frequencies were compared among NSCL±P patients and controls using Fisher exact test, implemented in PLINK software. The level of significance was established at P ≤.002 under Bonferroni correction. In silico analysis of SNP function was assessed using MirSNP database.RESULTS:Significant association was found between GSK3B rs13314595 genotypes and NSCL±P ( P = .0006). Additionally, nominal associations were found between DVL2 (rs35594616) and APC (rs448475) with NSCL±P ( P = .02 and P = .03, respectively). SNP haplotypes for GSK3B and APC genes showed nominal associations with NSCL±P ( P < .05). In silico analysis predicted that APC rs448475 harbors a binding site for the microRNA miR-617 and that the switch from a G allele to C allele enhances binding, whereas DVL2 rs35594616 did not appear to harbor microRNA-binding sites.CONCLUSION:This study shows for the first time the association between GSK3B and NSCL±P and confirms the role of additional WNT pathway genes as candidates for NSCL±P.

Romantic Matchmaking By Machine?

By Chordboard - Self, from material in my possession., Public Domain, https://commons.wikimedia.org/w/index.php?curid=4310843

For Valentine’s Day: an analysis of the shortcomings of machine learning (for now) to gauge two people’s romantic attraction to each other.  The authors divide romantic attraction into three components. First, the overall tendency of someone to desire others (actor variance), the tendency of that someone to be desired by others (partner variance) and, finally, a third component (relationship variance) that captures desire not characterized by the other two components (one may term this, I guess, “the mysteries of love”).  While machine leaning can predict some fraction of actor and partner variances, it was unable to model the more elusive relationship variance using traits and preferences reported before dates.  So far, the fine details of human romantic interest cannot be fully captured by machine learning. However, that may change in time.  Abstract:

Matchmaking companies and theoretical perspectives on close relationships suggest that initial attraction is, to some extent, a product of two people's self-reported traits and preferences. We used machine learning to test how well such measures predict people's overall tendencies to romantically desire other people (actor variance) and to be desired by other people (partner variance), as well as people's desire for specific partners above and beyond actor and partner variance (relationship variance). In two speed-dating studies, romantically unattached individuals completed more than 100 self-report measures about traits and preferences that past researchers have identified as being relevant to mate selection. Each participant met each opposite-sex participant attending a speed-dating event for a 4-min speed date. Random forests models predicted 4% to 18% of actor variance and 7% to 27% of partner variance; crucially, however, they were unable to predict relationship variance using any combination of traits and preferences reported before the dates. These results suggest that compatibility elements of human mating are challenging to predict before two people meet.

Janus-Faced Wnt Signaling

Deregulated Wnt signaling leads to certain types of cancer, particularly colorectal cancer.  But Wnt signaling is two-faced, Janus-faced, and certain neurological diseases are characterized by the opposite problem: repression of Wnt signaling.  There, inhibition of Wnt signaling enhances disease in a mouse model of Alzheimer’s.

Monoclonal Antibodies For Severe Asthma

By Adenosine - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9659630

Monoclonal antibodies are being used to treat many diseases, particularly cancer, and in this paper we see their utility for treating severe asthma. Different types of antibodies can be used dependent upon asthma type and characteristics, suggesting hope for people with the more serious forms of this disease.  Abstract:

Among the monoclonal antibodies (mAbs) developed for severe asthma treatment, three have already been marketed. Omalizumab was the first, more than 10 years ago; today, mepolizumab and reslizumab are also available in the European Union and the US. Omalizumab blocks free immunoglobulin E (IgE), mepolizumab and reslizumab block an interleukin (IL-5). In the near future, dupilumab and benralizumab are expected to emerge as two new alternatives. Benralizumab blocks the receptor for IL-5 (IL5-Rα) and has a direct cytotoxic effect on eosinophils, and dupilumab blocks the α-unit of the heterodimeric receptor for IL-4 and IL-13 (IL-4Rα); as a result, dupilumab can block both IL-4 and IL-13. The purpose of this manuscript is to present the pathophysiology of some immunological aspects of severe asthma, describe the adaptive and innate immunity arms as well as their interrelations (stressing the subordination of the adaptive arm to the innate arm), outline the pharmacologic effects of these mAbs, clarify the overlapping effects of the different mAbs, and discuss the differences between mAbs based on their target molecules. Based on the data presented, I propose omalizumab for patients with an allergic phenotype regardless of their peripheral eosinophilic count, and anti-IL-5 as an alternative in allergic patients with blood eosinophilia in which omalizumab has failed; anti-IL5 for patients with an eosinophilic phenotype and omalizumab as an alternative in patients in whom anti-IL5 fails and IgE ≥30 IU/mL (compassionate use). Omalizumab is also proposed for patients with severe chronic asthma allergic to seasonal allergens.

Chromatin Remodeling And Cancer Immunotherapy

CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=35818927

Immunotherapy against cancer is a promising treatment approach, but resistance is a problem. It has been shown that the expression of certain chromatin remodeling factors – that alter chromatin structure to affect gene expression – are associated with immunotherapy resistance in human cancer.  Inactivating these factors increases sensitivity to treatment, perhaps by altering the expression of genes that influence response to treatment.  This is an avenue of research that has clinical implications.  Abstract:

Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

Five years to live

What would you do if you have only five or ten years to live?

What would you regret about if the doctor tells you that you have only 24 hours to live?

Do you have a personal mission statement?

These are the questions asked by Paula and J.D. in this podcast episode of Afford Anything. I found the questions stirring.

If I had only five to ten years to live, I would put some money aside for my child (not too much!), quit my job (this very second) and the rest of my finances will be spent on traveling and having good times out there with whoever wants to be with me. Mom, child, spouse, a friend...

What would I be sorry about if I had only 24 hours to live? Missing on FUN. I need more fun in my life. My resolution right now is to start scheduling fun activities, rather than obligations.

I still do not have a personal mission statement and I may never have one. I like my ever-changing passions and interests. I have not come up with any statement that captures all my hopes. Isn't a mission statement more about hopes than reality?

Another great motivational video is this of Jenny Mustard. The main idea here is: do not establish and follow the routine! I need to start incorporating more activities in my life that make me happier. I might start a diary, or even better, work for five to ten minutes every night on projects of my imagination. I have a ton on projects either in their embryonic stage on my computer or brewing in my brain.

Speaking about things that bring me happiness and inspiration, here is a video on a great house. Architecture has always been a passion of mine.

Also, here is some hygge for the Spring!

I cannot wait for the snowdrops in my garden this spring season. These would be the first flowers to show in my garden. I dug out a few bulbs from the woods last year and this year, I am expecting the little white ballerinas to dance in front of the house. Maybe in February, maybe in March?
 
Since I have imposed a strict financial discipline on me, I have a restraining order away from flower catalogues; otherwise, I would have filled the garden with crocuses and hellebores. Unfortunately, tulips do not survive the hungry menagerie in my area.
 
Snowdrops and daffodils! As I imagine them nodding with the spring breeze, I smile. Yes, imagery is another way to happiness. Just imagine the sun, the blue sky and the little yellow daffodils.





What makes you feel happy and uplifted?

Tofu with cauliflower and carrots

I have never cooked tofu until today; however, recently I have realized that I need more protein in my diet.  After reading a few Internet concoctions with tofu, I invented my own.

Tofu with cauliflower and carrots
Ingredients:
1-2 heads of cauliflower, cut in small pieces
2 cups of baby carrots
extra firm tofu (size would depend on your preferences and the number of servings)
2 Tbsp of corn starch 
1-2 Tbsp honey (I used raw)
2 Tbsp olive oil
1 ½ cups soy sauce
To taste: crushed garlic, hot red pepper flakes, onion powder

Directions:
Remove the excess water from the block of tofu by blotting it between paper towels and topping it with a heavy pan. I did this for 30 minutes, during which I squeezed the water out of the towels once. Cut the tofu into cubes (approximately an inch in each dimension). Arrange the cubes on top of parchment paper. 
Wash the cauliflower and the baby carrots; mix them with some olive oil in a pan. Bake the veggies and the tofu at the same time at 400F. The tofu will be ready after 25-30 minutes and the veggies in 40 minutes. Midway baking, I mixed the vegetables; I also flipped each tofu piece.

The sauce was prepared with the rest of the recipe ingredients. I premixed the olive oil, soy sauce, honey, corn starch, garlic, onion powder and hot pepper flakes and heated the mix in a pan. After smoothing any clumps for 2-3 minutes, the sauce thickened and was ready to use.

Veggies and tofu were mixed together with the sauce and served!