My edit history statistics – includes my general editing statistics (e.g., monthly/yearly and cumulative edit counts), a list of pages I've edited the most, and a breakdown of my edits by namespace.
Some of my most notable contributions to Wikipedia:
Articles: This list includes articles in which I've written >80% of the source code (according to xTools' authorship attribution for the article) and for which I've spent the most time locating, reading, and citing WP:MEDRS-quality sources.
Lists: These pages contain a complete list of all known human protein-coding genes. I've been using a Python algorithm to regularly rewrite/update them.
Chinese-Wikipedia – zh:User:Seppi333 (I mainly assist with porting my contributions in articles/templates over to this Wikipedia; I can't read/write Chinese)
Quick summary of findings from a few of the teams:
Multiple teams implicated TTN in the pathophysiology of John's clinical phenotype (see here for a list of TTN mutations).
Two teams implicated TNXBhaploinsufficiency (technically, TNXB deficiency), manifesting as hypermobile Ehlers-Danlos syndrome, due to compound heterozygous frameshift mutations in this gene, both of which occur at tenascin-X glycine residue 362.
Several teams implicated genes associated with a congenital disorder of glycosylation; other genes related to lipid metabolism/storage, were also implicated in the etiology of his metabolic phenotype.
NB: I haven't yet looked into the genes implicated in the etiology of John's immunological phenotype, so I can't summarize this.
The following symptoms that John experiences are associated with TNXB loss of function mutations: NB: complete TNXB deficiency normally causes classic-like EDS and manifests with a much more pronounced phenotype than what John experiences; his clinical phenotype is much more similar to hypermobile EDS, most notably due to an apparently complete lack of skin involvement, so it would seem that John's genotype is not fully penetrant for clEDS.
elevated plasma histamine (likely reflects the involvement of mast cell disorders in EDS per [2])
Hackathon teams that identified the biallelic frameshift variants in his TNXB gene: Genobank & Tenacity (PPT) – both found it with Qiagen's proprietary Ingenuity Variant Analysis software.
Collapsed since I was looking primarily for sources on TNXB haploinsufficiency at the time. Seppi333 (Insert 2¢) 14:43, 20 May 2020 (UTC)
PubMed search link for ("TNXB"[Title/abstract] OR "tenascin-X"[Title/abstract] OR "tenascin X"[Title/abstract]) AND ("EDS"[Title/abstract] OR "Ehlers-Danlos syndrome"[Title/abstract] OR "joint hypermobility"[Title/abstract])
Primary study (2003): Haploinsufficiency of TNXB Is Associated with Hypermobility Type of Ehlers-Danlos Syndrome "Clinically, patients with reduced TNX levels showed hypermobile joints, often associated with joint subluxations and chronic musculoskeletal pain (table 1). The clinical findings in these patients differ from those with complete TNX deficiency. Patients with haploinsufficiency do not have skin hyperextensibility and lack the easy bruising seen in patients with TNX deficiency. In addition, TNXB haploinsufficiency is expected to be an autosomal dominant trait, which is in accordance with the observed mode of inheritance of HT-EDS and BJHS."
Primary study (2013): Tenascin-X Haploinsufficiency Associated with Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia (NB: the TNXB gene overlaps the CYP21A2 gene at its 3' ends; this paper is about mutations which affect both TNXB/CYP21A2, resulting in CAH & EDS) "Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings. → high penetrance of haploinsufficiency
Primary study (2019): Measurement of Serum Tenascin-X in Joint Hypermobility Syndrome Patients "In conclusion, we found out that sTNX concentrations in half of the 17 JHS/hEDS patients were significantly lower than those in healthy individuals and there were no mutations, insertions or deletions in TNXB except for one patient. At present, the reason for reduction in sTNX concentration without mutations of TNXB is not clear, but the expression of TNX might be affected by epigenetic changes that occur in the JHS/hEDS patients. Therefore, the results indicate that measurement of the sTNX concentration in patients with JHS/hEDS is beneficial and the decrease in sTNX concentration could be used as a risk factor for JHS/hEDS." – might be worth getting a TNXB ELISA if the antibody can actually bind to John’s mutant tenascin-X proteins, but altered protein function needs to be considered.
Review (2018): Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome. "Rarely, patients with severe, salt-wasting CAH have deletions of CYP21A2 that extend into TNXB, resulting in a "contiguous gene syndrome" consisting of CAH and EDS. Heterozygosity for TNXB mutations causing haploinsufficiency of TNX may be associated with the mild "hypermobility form" of EDS, which principally affects small and large joints. Studies of patients with salt-wasting CAH found that up to 10% had clinical features of EDS, associated joint hypermobility, haploinsufficiency of TNX and heterozygosity for TNXB mutations, now called 'CAH-X.'"
Primary study (2016): Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia "Hypermobility type EDS is the mildest EDS subtype with generalized joint hypermobility, recurrent joint dislocations and chronic arthralgias can occur, and mild skin manifestations such as smooth, velvety skin may also be present. The genetic etiology of hypermobility type EDS is largely unknown (De Paepe and Malfait, 2012; Sobey, 2014). In this report, we describe a subtype of EDS in CAH patients with biallelic TNXB variants that clinically resembles the classical type EDS phenotype. Prior studies of patients with CAH and monoallelic TNXB variants reported a phenotype similar to the hypermobility type EDS (Merke, et al., 2013; Morissette, et al., 2015). ... This study describes a biallelic form of CAH-X syndrome that is clinically and biochemically more severe than the monoallelic forms previously described (Merke, et al., 2013; Morissette, et al., 2015). We have chosen to use the terminology “biallelic”, rather than “autosomal recessive” to describe our CAH patients with TNXB variants on both alleles because the term “autosomal recessive” by definition implies that having a deleterious variant on one allele does not result in a clinical phenotype. Clearly this is not the case with CAH-X. Similarly, biallelic variants of well-established autosomal dominant disorders resulting in a more severe phenotype have been described in polycystic kidney disease (Bergmann, et al., 2011; Hopp, et al., 2012; Sandford, 2009), familial hypercholesterolemia (Varret, et al., 2008) and inherited cancers (Rahman and Scott, 2007). Thus, our findings reflect complex genetic heterogeneity not unexpected. ... However, the development of in vitro constructs for probing variants in TNX and the effect on its mechanism of action would provide useful functional information."
Given what the Ehlers-Danlos society has written about the association between TNXB haploinsufficieny and hypermobile EDS as well as TNXB deficiency and classical-like EDS − and that John's clinical phenotype is more characteristic of hEDS diagnosis while his genotype is diagnostic for clEDS due to complete TNXB deficiency − this actually seems more of a research issue than a diagnostic one. Hence, have referred him to contact the EDS society directly for assistance with his case. Seppi333 (Insert 2¢) 03:27, 18 May 2020 (UTC)
Pending analysis (2nd) - pending admission, I'm just leaving this to the UDN; otherwise, I'll construct a customized GCP pipeline to do my own hybrid assembly, use a novel non-DeepVariant, AI-based variant caller, and then annotate the variants with both pre-existing software as well as my own NLP-based content similarity approach using an annotation database and the medical records textract files to do my own analysis. Then, will compare to Hackathon teams that focused their analysis on this subset of protein-coding genes.
inability to gain body fat or lean mass despite consuming sufficient calories (symptom is highly responsive to chronic benzodiazepine use, during which it largely resolves [i.e., results in a gain of ~10-20 pounds of body mass]; body weight eventually returns to an abnormally low baseline upon cessation of benzodiazepine use)
multiple abnormally high glycosylphosphatidylinositide (GPI-anchored) lipid biomarkers – metabolome profiling revealed over half a dozen GPI-anchored lipids with serum concentrations of ~3σs above their population means
I don't have a working knowledge of immune defense against viral pathogens and only a basic understanding for fungal pathogens, so I haven't gone through these hackathon analyses.
Pending analysis (3rd) - pending admission, I'm just leaving this to the UDN; otherwise, I'll see if I can augment the analyses from the hackathon with a hybrid nanopore/Illumina assembly and apply the suggested types of variant callers mentioned in the presentations.
Four possible cases of stationarity and nonstationarity (with an I(1) unit root) for regressors and the error term (yt=α+βxt+μt). The time-series behavior of y is governed by the behavior of x and μ:
25 Nov 2024 – RMIT School of Medical Sciences(talk · edit · hist) was PRODed by Sgroey (t · c): School no longer exists, it is a one sentence page with no references. This school has been merged into the School of Health and biomedical sciences.
20 Nov 2024 – Multifunctional peptide(talk · edit · hist) was PRODed by WeirdNAnnoyed (t · c): A WP:DICTDEF and not even an accurate one...the term "multifunctional peptide" is used to mean many different things in biochemistry, including the definition given but also peptides that have more than one function, peptides chemically mod ... and endorsed by Bearian (t · c) on 22 Nov 2024
<ref name="NHMH_3e-#">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE, Holtzman DM | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2015 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071827706 | edition = 3rd | chapter = Chapter #:XYZ | quote= }}</ref>
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter #:XYZ". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. XX–YY. ISBN9780071481274.
^Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter #:XYZ". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN9780071827706.
^Wooldridge, Jeffrey (2012). "Chapter #: XYZ". Introductory Econometrics: A Modern Approach (5th ed.). South-Western Cengage Learning. pp. XX–YY. ISBN9781111531041.
^Greene, William (2012). "Chapter #: XYZ". Econometric Analysis (7th ed.). Pearson Education. pp. XX–YY. ISBN9780273753568.
{{cns}} – Generates a CN tag with text span to highlight specific text that requires citations. Ex: {{cns|this text}} generates this text[citation needed]
PMID 26180194 – Primary research paper that used novel statistical methodology to assess the dose-dependent effects of amphetamine on PFC-dependent working memory function
^Kennedy DO (January 2016). "B Vitamins and the Brain: Mechanisms, Dose and Efficacy-A Review". Nutrients. 8 (2). doi:10.3390/nu8020068. PMC4772032. PMID26828517. Furthermore, evidence from human research clearly shows both that a significant proportion of the populations of developed countries suffer from deficiencies or insufficiencies in one or more of this group of vitamins, and that, in the absence of an optimal diet, administration of the entire B-vitamin group, rather than a small sub-set, at doses greatly in excess of the current governmental recommendations, would be a rational approach for preserving brain health. ... RDAs are population statistics and they therefore represent rough estimates of the average requirement of individuals within a group/population, with an adjustment for the variations in the need for the nutrient among the individuals that make up the population. However, for most micronutrients some of the information that would be required to accurately calculate the daily requirement is either unknown or incomplete, and the recommendations are therefore made on the basis of a number of assumptions and considerations that could lead to large variations in the eventual RDA [81,82]. These figures have also changed little in the last four decades, despite emerging evidence of striking individual differences in the absorption and excretion of vitamins as a consequence of a wide range of factors, including specific genetic polymorphisms, gender, ethnicity, endocrine dysfunction, thyroid function, the habitual co-consumption of medicines, drugs, alcohol and other dietary factors, obesity, overall energy consumption, vigorous exercise, and age [9,21,45,83,84,85,86]. These gaps in our knowledge question the very existence of a "normal" population [87], and suggest that RDAs are, to some extent, arbitrary figures. Government figures also show that sizeable minorities of the populations of developed countries fail to consume even the minimum recommended quantity of any given micronutrient. As an example, Troesch et al. [88] presented data showing that a sizeable proportion of the populations of the US and several European countries consume less than the RDA for each of the five B vitamins that they assessed. They note that "a gap exists between vitamin intakes and requirements for a significant proportion of the population". As a result, studies assessing the blood levels of vitamins show that small but significant proportions of the populations of developed countries have biochemical levels of each of the B vitamins that may well predispose them to deficiency related diseases. ... For instance, recent US government data [91] demonstrated that 10.5% of the entire US population were biochemically deficient in vitamin B6. A subsequent independent analysis that excluded the substantial minority taking supplements containing vitamin B6 demonstrated much higher deficiency rates of between 23% and 27% for adults, depending on age [16].{{cite journal}}: CS1 maint: unflagged free DOI (link)
^Bragg DA, Walling A (2015). "Metabolic Syndrome: Hyperlipidemia". FP Essent. 435: 17–23. PMID26280341. When metabolic syndrome includes lipid abnormalities, management goals are weight loss and cardiovascular risk management through lifestyle modifications (eg, diet, exercise), and, when appropriate, lowering of lipid levels with pharmacotherapy. ... Lipid levels should be reevaluated 4 to 12 weeks after initiating therapy; lipid levels can be measured without fasting. A lack of improvement often indicates nonadherence. Bile acid sequestrants, fibric acids, and niacin can be used if other drugs are not tolerated.
^McCarty MF, DiNicolantonio JJ (2014). "The molecular biology and pathophysiology of vascular calcification". Postgrad Med. 126 (2): 54–64. doi:10.3810/pgm.2014.03.2740. PMID24685968. Vascular calcification (VC), commonly encountered in renal failure, diabetes, and aging, is associated with a large increase in the risk for cardiovascular events and mortality. Calcification of the arterial media and of heart valves clearly plays a mediating role in this regard, whereas it is less clear how calcification of plaque influences atherogenesis and risk for plaque rupture. Vascular calcification is an active process in which vascular smooth muscle cells (VSMCs) adopt an osteoblastic phenotype and deposit hydroxyapatite crystals; apoptosis of VSMCs also promotes this deposition. Drivers of this phenotypic transition, which include elevated serum phosphate, advanced glycation end-products, bone morphogenetic proteins, inflammatory cytokines, and leptin, invariably induce oxidative stress in VSMCs ... Antioxidants that suppress reduced nicotinamide adenine dinucleotide phosphate oxidase activity may have the potential to block the osteoblastic transition of VSMCs. Minimizing the absorption of dietary phosphate may also be helpful in this regard, particularly in renal failure, and it can be achieved with plant-based dietary choices, avoidance of phosphate additives, and administration of pharmaceutical phosphate binders, supplemental magnesium, and niacin.
Cognitive control deteriorates (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control)[1] as a result of:
^ abcdefghijDiamond A (2013). "Executive functions". Annu Rev Psychol. 64: 135–168. doi:10.1146/annurev-psych-113011-143750. PMC4084861. PMID23020641. Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control). ... EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory control (one of the core EFs) involves being able to control one's attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what's more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn't make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice.
^ abIlieva IP, Hook CJ, Farah MJ (January 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J. Cogn. Neurosci.: 1–21. doi:10.1162/jocn_a_00776. PMID25591060. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
^ abSpencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biol. Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMID25499957. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation. ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.{{cite journal}}: CS1 maint: year (link)
^ abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 318, 321. ISBN9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ... Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention. Drugs used for this purpose include, as stated above, methylphenidate, amphetamines, atomoxetine, and desipramine.
Citations to read through later
[3] - mentions the effects of long-term stimulant use on the cerebellum
(Page statistics) – became a featured article in January 2015
(most of this article's source is transcluded from the amphetamine article) – became a good article in December 2014
(Page statistics) – this article is still a work in progress
