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PubMed research · Cited sources
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PubMed research · Cited sources
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Three-dimensional prediction of T-cell receptor–peptide–major histocompatibility complex (TCR–pMHC) structures has progressed substantially, but accuracy remains dependent on the modeling strategy, complex type, structural feature, and evaluation metric. Flexible-backbone docking, specialized comparative-modeling pipelines, multimeric deep-learning architectures, and ensemble-generation methods have each addressed distinct limitations. TCRpMHCmodels, TCRmodel2, AlphaFold2, and AlphaFold3 have shown strong performance in different settings, while HADDOCK and specialized docking protocols can benefit from informative interface restraints or characteristic TCR–pMHC geometry. Nevertheless, CDR3 loops, peptide positioning, docking orientation, interface geometry, MHC class II complexes, and binding-affinity or specificity inference remain difficult. Global structural similarity may therefore obscure biologically important local errors. Current predictors are most appropriately used as complementary, hypothesis-generating tools, with model assessment based on multiple global, interface-focused, and functional criteria and with experimental validation retained as an essential step.
Question: performance of 3d structure prediction methods on TCR-pMHC complexes
Read the full reviewThe supplied evidence indicates that pioglitazone and related PPARγ agonists promote adipogenic remodeling, but it does not resolve whether they recruit primitive adipose stem cells, commit previously uncommitted progenitors, or primarily differentiate pre-existing committed preadipocytes. The strongest direct evidence is a short-term deuterium-labeling study showing increased generation of cells in both mature adipocyte and stromal-vascular compartments during pioglitazone exposure, consistent with precursor involvement and new adipocyte production (PMID: 22124466). However, the heterogeneous stromal-vascular fraction, absence of lineage tracing, and limited treatment duration prevent identification of the responsible progenitor population or assessment of long-term self-renewal. Related studies support PPARγ-dependent adipogenic differentiation, matrix remodeling, and possible clonal expansion in experimental systems, but remain indirect for pioglitazone action in normal human adipose tissue (PMID: 16799780; PMID: 16873539; PMID: 21572083; PMID: 12529376; PMID: 28957413). Overall, differentiation of adipogenically competent precursor cells is the best-supported interpretation, whereas recruitment of primitive stem cells and preservation of durable progenitor self-renewal remain unproven.
Question: does pioglitazone recruit proliferating adipose stem cells, commit uncommitted progenitors, or merely terminally differentiate an existing committed preadipocyte pool? what evidence from lineage tracing, deuterium labeling, clonal analysis, or serial human biopsies indicates whether chronic treatment preserves progenitor self-renewal and long-term hyperplastic capacity?
Read the full reviewPioglitazone improves insulin sensitivity and promotes subcutaneous adipose storage, but its ability to preferentially increase femoral rather than abdominal adipogenesis remains incompletely established. Human evidence indicates that pioglitazone can stimulate formation of new adipocytes in femoral subcutaneous fat while reducing relative visceral adiposity in women with obesity, although other studies demonstrate increased total subcutaneous fat without proving femoral selectivity (PMID: 33001232; PMID: 11887166; PMID: 12050251; PMID: 19910937; PMID: 21272186). Potential complementary pathways include adiponectin–AMPK signaling, 11β-HSD1/cortisol reduction, dietary fatty-acid optimization, BMP-mediated progenitor recruitment, angiogenesis, extracellular-matrix remodeling, insulin signaling, FGF21, and α2-adrenergic mechanisms. Adiponectin–AMPK offers the best balance of metabolic plausibility, reversibility, and safety, whereas depot-targeted BMP signaling has the greatest theoretical selectivity but limited translational support. Reducing abdominal glucocorticoid drive may improve the femoral-to-abdominal ratio indirectly by restraining abdominal expansion. No cited human study has directly tested these combinations or established a femoral-to-abdominal adipogenesis ratio. Accordingly, these strategies remain hypothesis-generating and should prioritize regional adipose measurements, edema surveillance, fibrosis assessment, and progenitor biology.
Question: which modifiable pathways could synergize with pioglitazone to increase the femoral-to-abdominal adipogenesis ratio—α2-adrenergic signaling, 11β-HSD1/cortisol, insulin, adiponectin–AMPK, FGF21, BMP signaling, angiogenesis, extracellular-matrix remodeling, or specific dietary fatty acids? rank candidates by depot selectivity, human evidence, expected effect size, reversibility, and risks such as generalized fat gain, edema, fibrosis, or progenitor depletion.
Read the full reviewDuring caloric surplus, pioglitazone could plausibly increase the storage capacity of subcutaneous adipose tissue through PPARγ activation, improved insulin sensitivity, adipocyte differentiation, and adipose remodeling. A mixed meal could theoretically combine chylomicron-triacylglycerol delivery with insulin-stimulated glucose uptake, glycerol-3-phosphate availability, suppression of lipolysis, and triacylglycerol re-esterification. However, the supplied evidence does not demonstrate that pioglitazone, meal composition or timing, postprandial insulin, gluteal resistance exercise, local heat, or altered adipose blood flow selectively increases femoral uptake or long-term trapping of meal-derived fatty acids. The proposed mechanism would require coordinated, depot-specific activity of lipoprotein lipase (LPL), CD36, acyl-CoA synthetase long-chain enzymes (ACSL), and diacylglycerol acyltransferase (DGAT), together with sufficient perfusion and intracellular retention. Skeletal muscle may compete for circulating fatty acids after exercise, and increased uptake must be distinguished from net retention and chronic adipocyte expansion. Overall, selective femoral partitioning remains a mechanistic hypothesis rather than an established intervention effect (PMID: 21721180; PMID: 23949610; PMID: 25969149; PMID: 27539147).
Question: during caloric surplus, can meal composition or timing, postprandial insulin, glute resistance exercise, local heat, or altered adipose perfusion selectively increase femoral uptake and trapping of meal-derived fatty acids during pioglitazone treatment? evaluate LPL, CD36, ACSL, DGAT, adipose blood flow, re-esterification, and skeletal-muscle competition, and distinguish acute substrate uptake from lasting adipocyte hyperplasia.
Read the full reviewDifferential responsiveness to pioglitazone among human adipose progenitors is best interpreted as variation in PPARγ pathway competence within distinct depot-specific developmental and cellular contexts. The available evidence does not support total PPARG abundance, or alternative PPARG isoform usage alone, as a sufficient explanation. Instead, PPARG2 induction and activity, RXR heterodimer competence, adipogenic commitment, BMP–WNT signaling, developmental identity, extracellular-matrix properties, and inflammatory or vascular context may interact to establish different thresholds for terminal adipogenesis. The strongest direct evidence concerns depot-dependent adipogenic competence and WNT-related regulation, including LRP5-associated effects in paired gluteal and abdominal progenitors (PMID: 25651180). Evidence from subcutaneous–omental comparisons further indicates that PPARG expression, PPARG2 inducibility, and RXRα availability may contribute, although these findings remain an extrapolation for femoral/gluteal–abdominal comparisons (PMID: 11872672; PMID: 9399962). Overall, pioglitazone appears to act on pre-existing depot states rather than uniformly overcoming upstream constraints.
Question: in paired human femoral/gluteal and abdominal adipose progenitors, which molecular features explain differential responsiveness to pioglitazone—PPARG abundance or isoforms, RXR/coactivator availability, CEBPA, ZNF423, BMP–WNT signaling, HOX/TBX15 developmental identity, extracellular-matrix stiffness, vascularity, or inflammatory state—and which of these features are plausibly modifiable in vivo?
Read the full reviewBartter syndrome comprises a group of usually autosomal-recessive renal salt-wasting tubulopathies caused by impaired sodium, potassium, and chloride reabsorption, primarily in the thick ascending limb of Henle’s loop and, in some phenotypes, the distal nephron. Salt and volume depletion activate the renin–angiotensin–aldosterone system, producing hypokalemic, hypochloremic metabolic alkalosis, elevated renin activity, secondary hyperaldosteronism, polyuria, and usually normal or low blood pressure. Disease severity ranges from severe antenatal or neonatal disease with polyhydramnios, prematurity, dehydration, and growth impairment to milder classic presentations later in childhood or adulthood. Genetic heterogeneity contributes to variable urinary calcium excretion, nephrocalcinosis, hypomagnesemia, and extra-renal manifestations. Molecular testing supports diagnosis and subtype classification, while treatment requires individualized lifelong replacement of fluids and electrolytes, monitoring for renal complications, and, in selected patients, reduction of prostaglandin-mediated losses.
Question: Bartter
Read the full reviewBartter syndrome is a rare, genetically heterogeneous inherited renal salt-wasting disorder caused primarily by impaired sodium and chloride reabsorption in the thick ascending limb of the loop of Henle, with some subtypes involving the distal convoluted tubule. Transport defects produce extracellular-fluid depletion, activation of the renin–angiotensin–aldosterone system, and renal potassium and hydrogen-ion loss, resulting in hypokalemic, hypochloremic metabolic alkalosis despite normal or low blood pressure. Clinical severity ranges from life-threatening antenatal disease with polyhydramnios, prematurity, severe neonatal polyuria, and dehydration to milder childhood or adult presentations. Hypercalciuria and nephrocalcinosis are especially characteristic of antenatal and classic forms. Diagnosis relies on clinical and biochemical assessment, supplemented by genetic testing, while treatment requires individualized fluid and electrolyte replacement and, in selected patients, nonsteroidal anti-inflammatory therapy. Early recognition is particularly important in neonatal disease, in which salt and water losses can progress rapidly.
Question: Bartter diasease
Read the full reviewPsoriasis is a chronic, relapsing inflammatory disease for which permanent reversal or cure has not been demonstrated. Current treatments can produce substantial, sometimes complete, skin clearance and may permit prolonged remission after treatment withdrawal, particularly with targeted biologic therapies affecting the IL-23/Th17 pathway. However, relapse remains common, and clinical clearance does not necessarily eliminate the underlying susceptibility to renewed inflammation. Persistent inflammatory memory involving tissue-resident memory T cells and changes in the skin environment may contribute to recurrence. Emerging strategies targeting pathogenic resident cells, innate immune signaling, and tissue-level mechanisms show experimental promise but remain unproven in humans. The available evidence therefore supports effective disease control, remission, and possible disease modification rather than confirmed permanent eradication.
Question: Psoriasis reversal
Read the full reviewDrug dosing must be individualized because age, developmental maturity, body size, organ function, pharmacokinetics, pharmacodynamics, treatment modality, and therapeutic targets can substantially alter drug exposure and response. These considerations are particularly important in neonates, premature infants, children, patients with renal impairment, and critically ill patients receiving continuous renal replacement therapy (CRRT). Initial dosing is influenced mainly by volume of distribution, whereas maintenance dosing depends primarily on clearance. Renal and hepatic dysfunction, developmental changes, fluid shifts, and extracorporeal therapies can therefore require dose reduction, interval extension, or both. Drug-specific examples illustrate the range of dosing challenges, including weight-based acetaminophen dosing in children, indication- and formulation-dependent quetiapine dosing, schedule-dependent decitabine administration, postmenstrual-age-based netilmicin regimens, once-daily gentamicin, and pharmacokinetically guided colistin methanesulfonate therapy. Therapeutic drug monitoring and pharmacokinetic–pharmacodynamic modeling can improve exposure while limiting toxicity, although several regimens remain uncertain and require adherence to disease-specific protocols.
Question: Drugs doses
Read the full reviewHeart failure (HF) is a clinical syndrome caused by structural or functional cardiac abnormalities that impair ventricular filling or ejection, producing inadequate cardiac output, elevated filling pressures, or both. It may involve reduced systolic function, impaired diastolic relaxation and filling, or combined left-, right-, or biventricular dysfunction. Clinical manifestations commonly include dyspnea, fatigue, reduced exercise tolerance, pulmonary or systemic congestion, and peripheral edema. HF is particularly common in older adults, and its prevalence and healthcare burden have increased with population aging and improved survival after cardiovascular disease. Neurohormonal activation initially supports circulation but, when persistent, promotes vasoconstriction, fluid retention, adverse remodeling, and progressive myocardial dysfunction. Diagnosis combines clinical assessment with investigations that characterize ventricular function, congestion, contributing comorbidities, and etiology. Management is individualized and may include lifestyle and comorbidity management, diuretics, vasodilators, neurohormonal therapies, and selected device or exercise-based interventions. Treatment aims to relieve symptoms and congestion, prevent hospitalization, slow progression, and improve survival.
Question: Heart failure
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