Mechanistic and Kinetic Insights into OH-Initiated Atmospheric Oxidation of Hymexazol: A Computational Study.

Hymexazol is a volatile fungicide widely used in agriculture, causing its abundance in the atmosphere; thus, its atmospheric fate and conversion are of great importance when assessing its environmental impacts. Herein, we report a theoretical kinetic mechanism for the oxidation of hymexazol by OH radicals, as well as the subsequent reactions of its main products with O2 and then with NO by using the Rice-Ramsperger-Kassel-Marcus-based Master equation kinetic model on the potential energy surface explored at the ROCBS-QB3//M06-2X/aug-cc-pVTZ level. The predicted total rate constants ktotal(T, P) for the reaction between hymexazol and OH radicals show excellent agreement with scarcely available experimental values (e.g., 3.6 × 10-12 vs (4.4 ± 0.8) × 10-12 cm3/molecule/s at T = 300 K and P = 760 Torr); thus, the calculated kinetic parameters can be confidently used for modeling/simulation of N-heterocycle-related applications under atmospheric and even combustion conditions. The model shows that 3,4-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-5-yl (IM2), 3,5-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-4-yl (IM3), and (3-hydroxy-1,2-oxazol-5-yl)methyl (P8) are the main primary intermediates, which form the main secondary species of (3,4-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)dioxidanyl (IM4), (3,5-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-4-yl)dioxidanyl (IM7), and ([(3-hydroxy-1,2-oxazol-5-yl)methyl]dioxidanyl (IM11), respectively, through the reactions with O2. The main secondary species then can react with NO to form the main tertiary species, namely, (3,4-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)oxidanyl (P19), (3,5-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-4-yl)oxidanyl (P21), and [(3-hydroxy-1,2-oxazol-5-yl)methyl]oxidanyl (P23), respectively, together with NO2. Besides, hymexazol could be a persistent organic pollutant in the troposphere due to its calculated half-life τ1/2 of 13.7-68.1 h, depending on the altitude.

OH-initiated oxidation of vinyl butyrate: ab initio insights.

The widespread use of vinyl butyrate (CH2CHOC(O)CH2CH2CH3 or VB) in the polymer industry and daily-life materials inevitably results in its emission into the atmosphere. Therefore, understanding the mechanism and kinetics of the VB conversion is critical for evaluating its fate and environmental impacts. Herein, we theoretically investigate the chemical transformation of VB initiated by OH radicals in the atmosphere using the stochastic Rice-Ramsperger-Kassel-Marcus (RRKM)-based master equation kinetic model on the potential energy surface explored at the M06-2X/aug-cc-pVTZ level of theory. Showing excellent agreement with limited experimental kinetic data, the VB + OH kinetic model reveals that H-abstraction from Cß (i.e., -CßH2CH3) prevails over the OH-addition to the double bond (CC), even at low temperatures. The detailed analyses, including those of the time-resolved species profiles, reaction rate, and reaction flux, reveal the reaction mechanism shift with temperature (causing the U-shaped temperature dependence of k(T, P)) and the noticeable pressure dependence of k(T, P) at low temperatures. The secondary chemistry under atmospheric conditions (namely, the reaction of the main product with O2 and its subsequent reactions with NO) was then characterized within the same framework to reveal the detailed kinetic mechanism (e.g., [4-(ethenyloxy)-4-oxobutan-2-yl]oxidanyl (IM12) + NO2 is the dominant channel under atmospheric conditions), suggesting VB is not a persistent organic pollutant and a new environmental concern regarding the formed NO2. Also, the kinetic behaviors of vinyl butyrate and its oxidation products were extended from atmospheric to combustion conditions for further applications. Moreover, through TD-DFT calculations, it is shown that several related important species (i.e., 1-(ethenyloxy)-1-oxobutan-2-yl (P4), [4-(ethenyloxy)-4-oxobutan-2-yl]dioxidanyl (IM7), and IM12) can potentially undergo photolysis in the atmosphere.

Reconstruction of Large Anterior Skull Base Defects After Resection of Sinonasal Tumors With Intracranial Extension by Using Pedicled Double Flap Techniques.

INTRODUCTION: The use of surgical resection for large anterior skull base (ASB) tumors and sinonasal malignancies with intracranial extension will result in a large skull base defect. Reconstruction of large ASB defects using traditional techniques is high risk and may lead to postoperative cerebral spinal fluid (CSF) leakage, meningitis, and an increase in mortality rate. The use of a pedicled double flap technique to reconstruct the ASB defect may decrease complications. This study presents the clinical outcomes of patients who underwent double flap reconstruction techniques after resection of their sinonasal malignancies with significant intracranial extension at Cho Ray hospital in Vietnam. METHODS: The case series study was conducted at Cho Ray hospital from September 2010 to September 2020. All patients with large sinonasal malignancies that invaded intracranially underwent transnasal endoscopic surgery and subfrontal craniotomy. Reconstruction of large skull base defects (>2 cm) were followed up by using the pedicled double flaps technique. This study was performed in line with the principles of the Declaration of Helsinki. Approval of the study was granted by the Independent Ethics Committee of Cho Ray Hospital (Date: March 3, 2014/No: 11/BVCRHDDD). RESULTS: During September 2010 to September 2020, there were 75 patients who underwent a modified multilayer, double flap reconstruction technique after the resection of their ASB tumor. Skull base defects were commonly seen along the horizontal plate of the ethmoid bone and the ethmoid roof (98.6%). Large skull base defects (>2 cm) accounted for 81.3% of cases. Overall, the risk of postoperative CSF leakage and meningitis after double flap repair was considerably low. Of all participants, only 1 experienced postoperative CSF leakage and 1 experienced postoperative meningitis. Despite the complications, these patients improved significantly and remained stable. CONCLUSION: The use of double vascularized pedicled flaps may decrease the incidence of postoperative CSF leakage and meningitis. This technique is an effective method for the reconstruction of ASB tumors with large defects.

Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney.

The development of the kidney relies on the establishment and maintenance of a precise tubular diameter of its functional units, the nephrons. This process is disrupted in polycystic kidney disease (PKD), resulting in dilations of the nephron and renal cyst formation. In the course of exploring G-protein-coupled signaling in the Xenopus pronephric kidney, we discovered that loss of the G-protein α subunit, Gnas, results in a PKD phenotype. Polycystin 1, one of the genes mutated in human PKD, encodes a protein resembling a G-protein-coupled receptor. Furthermore, deletion of the G-protein-binding domain present in the intracellular C terminus of polycystin 1 impacts functionality. A comprehensive analysis of all the G-protein α subunits expressed in the Xenopus pronephric kidney demonstrates that polycystin 1 recruits a select subset of G-protein α subunits and that their knockdown - as in the case of Gnas - results in a PKD phenotype. Mechanistically, the phenotype is caused by increased endogenous G-protein ß/γ signaling and can be reversed by pharmacological inhibitors as well as knocking down Gnb1. Together, our data support the hypothesis that G proteins are recruited to the intracellular domain of PKD1 and that this interaction is crucial for its function in the kidney.

Multi-parametric MRI of kidney disease progression for autosomal recessive polycystic kidney disease: mouse model and initial patient results.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare but potentially lethal genetic disorder typically characterized by diffuse renal microcysts. Clinical trials for patients with ARPKD are not currently possible due to the absence of sensitive measures of ARPKD kidney disease progression and/or therapeutic efficacy. METHODS: In this study, animal and human magnetic resonance imaging (MRI) scanners were used to obtain quantitative kidney T1 and T2 relaxation time maps for both excised kidneys from bpk and wild-type (WT) mice as well as for a pediatric patient with ARPKD and a healthy adult volunteer. RESULTS: Mean kidney T1 and T2 relaxation times showed significant increases with age (p < 0.05) as well as significant increases in comparison to WT mice (p < 2 × 10-10). Significant or nearly significant linear correlations were observed for mean kidney T1 (p = 0.030) and T2 (p = 0.054) as a function of total kidney volume, respectively. Initial magnetic resonance fingerprinting assessments in a patient with ARPKD showed visible increases in both kidney T1 and T2 in comparison to the healthy volunteer. CONCLUSIONS: These preclinical and initial clinical MRI studies suggest that renal T1 and T2 relaxometry may provide an additional outcome measure to assess cystic kidney disease progression in patients with ARPKD. IMPACT: A major roadblock for implementing clinical trials in patients with ARPKD is the absence of sensitive measures of ARPKD kidney disease progression and/or therapeutic efficacy. A clinical need exists to develop a safe and sensitive measure for kidney disease progression, and eventually therapeutic efficacy, for patients with ARPKD. Mean kidney T1 and T2 MRI relaxation times showed significant increases with age (p < 0.05) as well as significant increases in comparison to WT mice (p < 2 ×10-10), indicating that T1 and T2 may provide sensitive assessments of cystic changes associated with progressive ARPKD kidney disease. This preclinical and initial clinical study suggests that MRI-based kidney T1 and T2 mapping could be used as a non-invasive assessment of ARPKD kidney disease progression. These non-invasive, quantitative MRI techniques could eventually be used as an outcome measure for clinical trials evaluating novel therapeutics aimed at limiting or preventing ARPKD kidney disease progression.

Iodine-Catalyzed Synthesis of Substituted Furans and Pyrans: Reaction Scope and Mechanistic Insights.

Substituted pyrans and furans are core structures found in a wide variety of natural products and biologically active compounds. Herein, we report a practical and mild catalytic method for the synthesis of substituted pyrans and furans using molecular iodine, a simple and inexpensive catalyst. The method described is performed under solvent-free conditions at an ambient temperature and atmosphere, thus offering a facile and practical alternative to currently available reaction protocols. A combination of experimental studies and density functional theory calculations revealed interesting mechanistic insights into this seemingly simple reaction.

Removal of total nitrogen from wastewater by a combination of Chlorella sp. and audible sound.

In developing countries, nitrogen in the traditional market wastewater is a critical environmental problem. In this study, the microalga Chlorella sp., which was isolated from wastewater, was used to remove the total nitrogen (TN) from conventional market wastewater in combination with audible sound (Vietnamese classical music). In addition, effects of sound exposure on removal efficiency at different initial cell densities were analyzed. Results revealed that music sound control demonstrates potential to improve the removal efficiency. TN removal efficiencies of 96%, 69.5%, and 4.3% were observed for treatments with Chlorella sp./audible sound, Chlorella sp., and without Chlorella sp., respectively. The significance of probability value (p-value) (<0.05) on the paired sample t-test confirmed the critical role of audible sound and Chlorella sp. density on the TN removal in screening experiments. The predicted optimal conditions for TN removal were as follows: a Chlorella sp. density of 4%, an audible sound of 52.5 dB, and a cultivation time of 4.6 days. Results based on statistical analysis revealed that the quadratic models for TN removal are significant at a low p-value (<0.05) and a high predicted coefficient of determination (R2 = 0.9452) value. The obtained statistical results also indicated that most of the variables are significant for the abatement of TN from market wastewater using Chlorella sp.

Catalytic Synthesis of Trifluoromethyl Cyclopropenes and Oligo-Cyclopropenes.

The synthesis of trifluoromethylated cyclopropenes is often associated with important applications in drug discovery and functional materials. In this report, we describe the use of readily available chiral rhodium(II) catalysts for a highly efficient asymmetric cyclopropenation reaction of fluorinated donor-acceptor diazoalkanes with a broad variety of aliphatic and aromatic alkynes. Further studies highlight the unique reactivity of fluorinated donor-acceptor diazoalkanes in the synthesis of oligo-cyclopropenes. Subsequent C-H functionalization of trifluoromethyl cyclopropenes furnishes densely substituted cyclopropene frameworks and also allows the alternative synthesis of bis-cyclopropenes.

Rewiring T-cell responses to soluble factors with chimeric antigen receptors.

Chimeric antigen receptor (CAR)-expressing T cells targeting surface-bound tumor antigens have yielded promising clinical outcomes, with two CD19 CAR-T cell therapies recently receiving FDA approval for the treatment of B-cell malignancies. The adoption of CARs for the recognition of soluble ligands, a distinct class of biomarkers in physiology and disease, could considerably broaden the utility of CARs in disease treatment. In this study, we demonstrate that CAR-T cells can be engineered to respond robustly to diverse soluble ligands, including the CD19 ectodomain, GFP variants, and transforming growth factor beta (TGF-ß). We additionally show that CAR signaling in response to soluble ligands relies on ligand-mediated CAR dimerization and that CAR responsiveness to soluble ligands can be fine-tuned by adjusting the mechanical coupling between the CAR's ligand-binding and signaling domains. Our results support a role for mechanotransduction in CAR signaling and demonstrate an approach for systematically engineering immune-cell responses to soluble, extracellular ligands.

Halide Anion Triggered Reactions of Michael Acceptors with Tropylium Ion.

Tropylium bromide undergoes noncatalyzed, regioselective additions to a large variety of Michael acceptors. In this way, acrylic esters are converted into ß-bromo-α-cycloheptatrienylpropionic esters. The reactions are interpreted as nucleophilic attack of bromide ions at the electron-deficient olefins and the approach of the tropylium ion to the incipient carbanion. Quantum chemical calculations were performed to elucidate the analogy to the amine- or phosphine-catalyzed Rauhut-Currier reactions. Subsequent synthetic transformations of the bromo-cycloheptatrienylated adducts are reported.

Zoonotic diseases from birds to humans in Vietnam: possible diseases and their associated risk factors.

In recent decades, exceeding 60% of infectious cases in human beings are originated from pathogenic agents related to feral or companion animals. This figure continues to swiftly increase due to excessive exposure between human and contaminated hosts by means of applying unhygienic farming practices throughout society. In Asia countries-renowned for lax regulation towards animal-trading markets-have experienced tremendous outbreaks of zoonotic diseases every year. Meanwhile, various epidemic surges were first reported in the residential area of China-one of the largest distributor of all animal products on the planet. Some noticeable illnesses comprising of A/H5N1 or H7N9-known as avian influenza which transmitted from poultry and also wild birds-have caused inevitable disquiet among inhabitants. Indeed, poultry farming industry in China has witnessed dynamic evolution for the past two decades, both in quantity and degree of output per individual. Together with this pervasive expansion, zoonotic diseases from poultry have incessantly emerged as a latent threat to the surrounding residents in entire Asia and also European countries. Without strict exporting legislation, Vietnam is now facing the serious problem in terms of poultry distribution between the two countries' border. Even though several disease investigations have been conducted by many researchers, the disease epidemiology or transmission methods among people remained blurred and need to be further elucidated. In this paper, our aim is to provide a laconic review of common zoonotic diseases spread in Vietnam, outstanding cases and several factors predisposing to this alarming situation.

The possible zoonotic diseases transferring from pig to human in Vietnam.

Southeast Asia is considered one of worldwide hotspots consisting many distinct zoonotic infections. With optimal condition for the development of various pathogens, Vietnam is facing serious risks of zoonotic diseases. Besides, more than 50% Vietnamese people settle in rustic areas and earn their livings through small-scale animal breeding. It is possible that zoonotic diseases can be easily spread to the population by close contact with the infected animals, their infected residues, contaminated water, soil, or other possible means of transmission. In fact, zoonotic infections-transmissible infections between vertebrate animals and humans-cover a wide range of diseases with distinctive clinical and epidemiological highlights. With insufficient understanding and swift alteration in toxicity of the pathogens, these infections have gained more concerns due to sophisticated routes of transmission and harmful threats to humans. Recently emerging viral diseases exerted potential dangers to human beings, which required many countries to impose immediate actions to prevent any complications. Vietnam has recorded several cases of zoonotic diseases, especially pig-related illnesses; however, the studies on these diseases in this country remain limited. This work aims to highlight the zoonotic diseases transferring from pigs to humans and discuss risk factors of these diseases in Vietnam.

The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in PKD1 (85%) or PKD2 (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor-ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors. Using yeast two-hybrid, biochemical, and cellular assays, we determined that PC2 binds two isoforms of the retromer-associated protein sorting nexin 3 (SNX3), including a novel isoform that binds PC2 in a direct manner. Knockdown of SNX3 or the core retromer protein VPS35 increased the surface expression of endogenous PC1 and PC2 in vitro and in vivo and increased Wnt-activated PC2-dependent whole-cell currents. These findings indicate that an SNX3-retromer complex regulates the surface expression and function of PC1 and PC2. Molecular targeting of proteins involved in the endosomal sorting of PC1 and PC2 could lead to new therapeutic approaches in ADPKD.

P2Y12 receptor inhibitor resistance and coronary artery disease: a bench to bedside primer for cardiovascular specialists.

PURPOSE OF REVIEW: Platelet P2Y12 receptor inhibitors are routinely prescribed for patients after acute coronary syndromes and percutaneous coronary interventions. Patients may have underresponsiveness (or resistance) to these drugs and in particular to clopidogrel, the most often used type. This review aims to focus on the concept of P2Y12 receptor inhibitor resistance and discuss incidence, mechanisms, novel diagnostic techniques and past and future clinical trials on the topic. RECENT FINDINGS: Patients treated with P2Y12 receptor inhibitors may develop high on-treatment platelet reactivity (HPR), a phenomenon of impaired response toward the drug, which has been associated with ischemic complications. Although potent P2Y12 inhibitors provide better ischemic protection, this must be balanced with increased bleeding risk. Several clinical factors, including common genetic variants such as Cytochrome P450 2C19 loss-of-function alleles, have been shown to predispose to HPR among patients on clopidogrel. Platelet function tests and genotyping platforms have enabled identification of patients at-risk for HPR. Past studies using platelet testing and tailoring therapy among patients with HPR have failed to provide conclusive data to support its routine use. SUMMARY: Ongoing studies using genotyping and novel antiplatelet regimens may identify potential strategies to minimize ischemic and bleeding risks concurrently. Until definitive studies demonstrate clear benefit of a personalized approach to P2Y12 inhibitor prescription, the choice of P2Y12 inhibitors should continue to be based on best evidence from previous large clinical trials.

Positive regulatory role of strigolactone in plant responses to drought and salt stress.

This report provides direct evidence that strigolactone (SL) positively regulates drought and high salinity responses in Arabidopsis. Both SL-deficient and SL-response [more axillary growth (max)] mutants exhibited hypersensitivity to drought and salt stress, which was associated with shoot- rather than root-related traits. Exogenous SL treatment rescued the drought-sensitive phenotype of the SL-deficient mutants but not of the SL-response mutant, and enhanced drought tolerance of WT plants, confirming the role of SL as a positive regulator in stress response. In agreement with the drought-sensitive phenotype, max mutants exhibited increased leaf stomatal density relative to WT and slower abscisic acid (ABA)-induced stomatal closure. Compared with WT, the max mutants exhibited increased leaf water loss rate during dehydration and decreased ABA responsiveness during germination and postgermination. Collectively, these results indicate that cross-talk between SL and ABA plays an important role in integrating stress signals to regulate stomatal development and function. Additionally, a comparative microarray analysis of the leaves of the SL-response max2 mutant and WT plants under normal and dehydrative conditions revealed an SL-mediated network controlling plant responses to stress via many stress- and/or ABA-responsive and cytokinin metabolism-related genes. Our results demonstrate that plants integrate multiple hormone-response pathways for adaptation to environmental stress. Based on our results, genetic modulation of SL content/response could be applied as a potential approach to reduce the negative impact of abiotic stress on crop productivity.

The Polycystin-1, Lipoxygenase, and α-Toxin Domain Regulates Polycystin-1 Trafficking.

Mutations in polycystin-1 (PC1) give rise to autosomal dominant polycystic kidney disease, an important and common cause of kidney failure. Despite its medical importance, the function of PC1 remains poorly understood. Here, we investigated the role of the intracellular polycystin-1, lipoxygenase, and α-toxin (PLAT) signature domain of PC1 using nuclear magnetic resonance, biochemical, cellular, and in vivo functional approaches. We found that the PLAT domain targets PC1 to the plasma membrane in polarized epithelial cells by a mechanism involving the selective binding of the PLAT domain to phosphatidylserine and L-α-phosphatidylinositol-4-phosphate (PI4P) enriched in the plasma membrane. This process is regulated by protein kinase A phosphorylation of the PLAT domain, which reduces PI4P binding and recruits ß-arrestins and the clathrin adaptor AP2 to trigger PC1 internalization. Our results reveal a physiological role for the PC1-PLAT domain in renal epithelial cells and suggest that phosphorylation-dependent internalization of PC1 is closely linked to its function in renal development and homeostasis.

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity.

Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2(Lp) compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2(Lp) mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2(Lp/+) enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2(Lp/+) embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2(Lp/Lp)) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos.

Sterol carrier protein 2 regulates proximal tubule size in the Xenopus pronephric kidney by modulating lipid rafts.

The kidney is a homeostatic organ required for waste excretion and reabsorption of water, salts and other macromolecules. To this end, a complex series of developmental steps ensures the formation of a correctly patterned and properly proportioned organ. While previous studies have mainly focused on the individual signaling pathways, the formation of higher order receptor complexes in lipid rafts is an equally important aspect. These membrane platforms are characterized by differences in local lipid and protein compositions. Indeed, the cells in the Xenopus pronephric kidney were positive for the lipid raft markers ganglioside GM1 and Caveolin-1. To specifically interfere with lipid raft function in vivo, we focused on the Sterol Carrier Protein 2 (scp2), a multifunctional protein that is an important player in remodeling lipid raft composition. In Xenopus, scp2 mRNA was strongly expressed in differentiated epithelial structures of the pronephric kidney. Knockdown of scp2 did not interfere with the patterning of the kidney along its proximo-distal axis, but dramatically decreased the size of the kidney, in particular the proximal tubules. This phenotype was accompanied by a reduction of lipid rafts, but was independent of the peroxisomal or transcriptional activities of scp2. Finally, disrupting lipid micro-domains by inhibiting cholesterol synthesis using Mevinolin phenocopied the defects seen in scp2 morphants. Together these data underscore the importance for localized signaling platforms in the proper formation of the Xenopus kidney.

The bigger the better: determining nephron size in kidney.

The main functions of the kidney are to excrete metabolic waste products and actively reabsorb essential molecules such as amino acids, ions, glucose and water. In humans, a wide range of genetic disorders exist characterized by wasting of metabolically important compounds. At the cellular level, more than 20 highly specialized renal epithelial cell types located in different segments of the nephron contribute to the reabsorption process. In particular, proximal tubular cells play a crucial role and are uniquely adapted to maximize reabsorption efficiency. They accommodate high numbers of transporters and channels by increasing the apical surface area in contact with the primary filtrate by forming a brush border as well as undergoing hypertrophy and hyperplasia. This adaptation is evolutionarily conserved and is detected in the primitive pronephric kidney of fish and amphibians as well as the metanephric kidney of higher vertebrates. Surprisingly, signaling pathways regulating these three processes have remained largely unknown. Here we summarize recent studies that highlight the early phases of kidney development as a critical juncture in establishing proximal tubule size.