Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects.

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [14C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [14C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Synergistic Enhancement of CO2 photoreduction through sulfur defects in (3D/2D) CdS-nanoflowers/CN Binary heterojunction photocatalyst under visible light.

Global warming is the biggest threat to the entire world owing to the continuous release of greenhouse gases such as CO2 from various sources. Herein, we have utilized renewable energy for the conversion of CO2 to valuable feedstocks through a semiconductor-mediated photocatalytic system. The cadmium sulfide nanoflowers (CS-NFs) decorated graphitic carbon nitride (CN) through a solvothermal route to form a Z-scheme CSCN heterojunction. The as-synthesized material has been characterized by various spectroscopic and microscopic tools. The optimal CSCN-0.5 (1:0.5) photocatalyst achieves a CO production rate of 130.9 µmol g-1 under visible light irradiation of 4h (λ > 420 nm), doubling that of pristine CS-NFs and CN. CO, along with CH4 (3.4 µmol g-1) and C2H6 (2.9 µmol g-1), is the sole product detected. Experimental results indicate that the CSCN-0.5 photocatalyst spatially separates electron-hole pairs, suppresses charge carrier recombination, and maintains robust redox ability, enhancing CO2 photoreduction. The CO2 reduction mechanism over CSCN heterojunction was also studied through in-situ DRIFTS and electron spin resonance (ESR) measurements. Therefore, CSCN proves that it could be used as a robust photocatalyst for the CO2 reduction reactions towards C1 and C2 feedstocks.

Random lasers from photonic crystal wings of butterfly and moth for speckle-free imaging.

Several biological membranes have been served as scattering materials of random lasers, but few of them include natural photonic crystals. Here, we propose and demonstrate a facile approach to fabricating high-performance biological photonic crystal random lasers, which is cost-effective and reproducible for mass production. As a benchmark, optical and lasing properties of dye-coated Lepidoptera wings, including Papilio ulysses butterfly and Chrysiridia rhipheus moth, are characterized and show a stable laser emission with a superior threshold of 0.016 mJ/cm2, as compared to previous studies. To deploy the proposed devices in practical implementation, we have applied the as-fabricated biological devices to bright speckle-free imaging applications, which is a more sustainable and more accessible imaging strategy.

In-situ preparation of CuO nanoparticles decorated In2O3 pn heterojunction composite for the photoelectrochemical detection of ornidazole.

The eco-friendly synthesis of metal oxides pn junction composite with high visible light absorption and its photoelectrochemical monitoring on antibiotics is reported. The In2O3-CuO pn heterojunction composite was successfully prepared by in-situ hydrothermal decoration of CuO on the prepared In2O3 using a simple reflux method. The obtained nanorods like In2O3-CuO pn heterojunction exhibited high conductivity with excellent stability for the facilitated photoelectrochemical detection of ornidazole (ONZ) that plays a role in aquatic toxicology. The photo-stability and optical characteristics of the In2O3-CuO heterojunction composite were analyzed through photocurrent and UV-visible studies. Mechanism of ONZ signaling has been proposed with appropriate band levels derived by Mott-Schottky analysis. An optimized In2O3-CuO heterojunction detects ONZ in the range 0.05-65.3 nM with 0.0092 nM as the limit of detection at - 0.45 V (vs. Ag/AgCl) working potential. The practical applicability of the sensor device was tested in chicken meat, human urine, and lake water samples containing ONZ. The recoveries of real samples were above 95% and results obtained were compared with electrochemical methods.

A Telesimulation Elective to Provide Medical Students With Pediatric Patient Care Experiences During the COVID Pandemic.

OBJECTIVES/INTRODUCTION: The Association of American Medical Colleges suggested that medical students not be involved in direct patient care activities in the United States because of the COVID pandemic. Our objectives are to (1) describe the rapid creation and implementation of a fully online simulation-based pediatric emergency medicine training intervention for medical student learners using existing simulation center staff (faculty, technicians, actors) and resources (simulation technology, scenario files) and (2) report student and faculty feedback on the intervention. METHODS: The sessions involved the use of our existing simulation center faculty, staff, and resources. Feedbacks on the sessions were collected via a survey from faculty and students at the end of each session. RESULTS: Sixteen simulation sessions were conducted (8 febrile infant, 8 anaphylactic toddler). Forty-eight students, 2 technicians, 2 actors, and 10 faculty participated. Ninety percent of the students agreed with the statements, "I am more comfortable with pediatrics after this session," "participating improved my pediatric knowledge/skills," "this session was more useful than other learning activities I am involved in at this time." Seventy percent of the students agreed with the statement, "I learned as much from observing as when I was actively involved." All faculty agreed with the statement, "this was an effective educational strategy compared to other distance learning." Most faculty (60%) disagreed with the statement, "virtual simulation was equal to or superior to in-person simulation." All students and faculty strongly agreed with the statement, "I would highly recommend this to others." CONCLUSIONS: A telesimulation intervention involving all medical students, staff, and facilitators interacting remotely for pediatric emergency training during COVID was associated with high levels of satisfaction by the majority of learners and faculty.

Early exposure to a methyl donor supplemented diet and the development of repetitive motor behavior in a mouse model.

Motor behaviors that are repetitive and exhibit little variability in form are common in neurodevelopmental disorders (e.g., autism spectrum disorder). C58 mice exhibit persistent, high levels of repetitive motor behavior when reared in restricted, but not enriched, environments implicating epigenetic mechanisms (e.g., DNA methylation). We sought to determine if alteration of DNA methylation played a role in the development of repetitive behavior in C58 mice. Thus, we tested the hypothesis that early exposure (in utero and preweaning) to a methyl donor supplemented diet would alter the developmental trajectory of repetitive behavior. Such dietary exposure resulted in significant attenuation of repetitive motor behavior development, persisting through early adulthood. This was despite mice being housed in standard cages and maintained on a standard diet, postweaning. Early exposure to methyl donor supplementation not only affected the frequency of repetitive behavior but also its temporal structure, resulting in more variable patterns of repetitive behavior. Early exposure to the diet was also shown to induce long-lasting increases in DNA methylation in brain tissue of female mice. The role for alterations in DNA methylation in this model may be one mechanism accounting for the robust effects of the environment on the development of repetitive behavior.

Biomass-Derived Porous Carbons Derived from Soybean Residues for High Performance Solid State Supercapacitors.

A series of heteroatom-containing porous carbons with high surface area and hierarchical porosity were successfully prepared by hydrothermal, chemical activation, and carbonization processes from soybean residues. The initial concentration of soybean residues has a significant impact on the textural and surface functional properties of the obtained biomass-derived porous carbons (BDPCs). SRAC5 sample with a BET surface area of 1945 m2 g-1 and a wide micro/mesopore size distribution, nitrogen content of 3.8 at %, and oxygen content of 15.8 at % presents the best electrochemical performance, reaching 489 F g-1 at 1 A g-1 in 6 M LiNO3 aqueous solution. A solid-state symmetric supercapacitor (SSC) device delivers a specific capacitance of 123 F g-1 at 1 A g-1 and a high energy density of 68.2 Wh kg-1 at a power density of 1 kW kg-1 with a wide voltage window of 2.0 V and maintains good cycling stability of 89.9% capacitance retention at 2A g-1 (over 5000 cycles). The outstanding electrochemical performances are ascribed to the synergistic effects of the high specific surface area, appropriate pore distribution, favorable heteroatom functional groups, and suitable electrolyte, which facilitates electrical double-layer and pseudocapacitive mechanisms for power and energy storage, respectively.

Prospective, Multicenter Feasibility Study to Evaluate Differential Target Multiplexed Spinal Cord Stimulation Programming in Subjects With Chronic Intractable Back Pain With or Without Leg Pain.

OBJECTIVE: This prospective, open-label, multicenter study evaluated the feasibility of spinal cord stimulation (SCS) therapy programming for chronic low back pain that uses multiple electrical pulsed signals (Differential Target Multiplexed). METHODS: Twenty-five SCS candidates with low back pain equal to or greater than lower limb pain were enrolled at 7 sites in the United States. The subjects evaluated standard and Differential Target Multiplexed programs, each for 4 ± 1 days. A commercially available SCS trial system was used for standard SCS therapy programming. During the trialing of the multiplexed programs, implanted temporary leads were connected to an investigational external trial stimulator system. RESULTS: Twenty subjects concluded the study. The mean baseline numeric pain rating scale (NPRS) score for low back pain was 7.4, with a mean age of 62.4 years and mean pain duration of 18.0 years. Significant relief in back pain was observed for both treatments, with significantly better response with multiplexed programming. At the end of the trial period, subjects reported a reduction in their mean NPRS score from baseline to 4.2 after standard programming and to 2.4 after Differential Target Multiplexed programming. The difference between standard and multiplexed programming was significant. The responder rate for low back pain relief was 50% for standard programming and 80% for Differential Target Multiplexed programming. Eighty-five percent of subjects who evaluated both programming approaches preferred Differential Target Multiplexed SCS. CONCLUSION: In this difficult-to-treat patient population, subjects reported significant reduction in chronic back pain when using multiplexed programming. A randomized clinical trial is needed to confirm the results from this feasibility study.

Adsorptive decontamination of diclofenac by three-dimensional graphene-based adsorbent: Response surface methodology, adsorption equilibrium, kinetic and thermodynamic studies.

Pharmaceutical residues are emerging pollutants in the aquatic environment and their removal by conventional wastewater treatment methods has proven to be ineffective. This research aimed to develop a three-dimensional reduced graphene oxide aerogel (rGOA) for the removal of diclofenac in aqueous solution. The preparation of rGOA involved facile self-assembly of graphene oxide under a reductive environment of L-ascorbic acid. Characterisation of rGOA was performed by Fourier transform infrared, scanning electron microscope, transmission electron microscopy, nitrogen adsorption-desorption, Raman spectroscopy and X-ray diffraction. The developed rGOA had a measured density of 20.39 ±â€¯5.28 mg/cm3, specific surface area of 132.19 m2/g, cumulative pore volume of 0.5388 cm3/g and point of zero charge of 6.3. A study on the simultaneous interactions of independent factors by response surface methodology suggested dosage and initial concentration as the dominant parameters influencing the adsorption of diclofenac. The highest diclofenac adsorption capacity (596.71 mg/g) was achieved at the optimum conditions of 0.25 g/L dosage, 325 mg/L initial concentration, 200 rpm shaking speed and 30 °C temperature. The adsorption equilibrium data were best fitted to the Freundlich model with correlation coefficient (R2) varying from 0.9500 to 0.9802. The adsorption kinetic data were best correlated to the pseudo-first-order model with R2 ranging from 0.8467 to 0.9621. Thermodynamic analysis showed that the process was spontaneous (∆G = - 7.19 to - 0.48 kJ/mol) and exothermic (∆H = - 12.82 to - 2.17 kJ/mol). This research concluded that rGOA is a very promising adsorbent for the remediation of water polluted by diclofenac.

In situ infrared study of photo-generated electrons and adsorbed species on nitrogen-doped TiO2 in dye-sensitized solar cells.

Charge transfer between adsorbed dyes and the TiO2 surface plays a key role in controlling the efficiency of dye-sensitized solar cells (DSSCs). The lack of understanding of charge transfer steps has hindered further development of DSSCs and many solar energy conversion devices/processes. In this study, we used in situ infrared spectroscopy to investigate electron transfer and photo-electric energy conversion processes at the interface, i.e., surface hydroxyls, adsorbed species, as well as the dynamics of photo-generated electrons in TiO2 and N-TiO2 in DSSCs. Nitrogen (N-) doping of TiO2 blocked linear OH, giving more hydrophobic surface characteristics than undoped TiO2. N-Doping further increased the electron-hole separation caused by solar light on the working electrode and the current density in the DSSC. In situ infrared (IR) studies revealed that N-doping facilitated the electron transfer from the N719 dye (di-tetrabutylammonium cis-bis(isothiocyanato)bis(2,2-bipyridyl-4,4-dicarboxylato)ruthenium(ii)) to the conduction band in TiO2, reducing the impedance in the DSSC. Probing N-TiO2 with adsorbed ethanol showed that shallow traps in N-TiO2 can be accessed by electrons from adsorbed ethanol. Electron transfer from the N719 dye is significantly faster than that from adsorbed ethanol which involves C-H bond breaking.

Long-term quality of life improvement for chronic intractable back and leg pain patients using spinal cord stimulation: 12-month results from the SENZA-RCT.

PURPOSE: Chronic axial low-back pain is a debilitating disorder that impacts all aspects of an afflicted individual's life. Effective, durable treatments have historically been elusive. Interventional therapies, such as spinal cord stimulation (SCS), have shown limited efficacy at best. Recently, a novel treatment, 10 kHz SCS, has demonstrated superior pain relief compared with traditional SCS in a randomized controlled trial (RCT). In this manuscript, we report on the long-term improvements in quality of life (QoL) outcomes for subjects enrolled in this study. METHODS: A prospective, multicenter, randomized controlled trial (SENZA-RCT) was conducted. Patients with both chronic back and leg pain were enrolled and randomized (1:1) into 10 kHz SCS or traditional SCS treatment groups. A total of 171 subjects received a permanent SCS device implant. QoL and functionality measures were collected up to 12 months. The device remote control utilization, which is an indication of patient interaction with the device for adjustments, was collected at 24-month post-implantation. RESULTS: At 12 months, a higher proportion of 10 kHz SCS subjects had marked improvement of their disability (Oswestry Disability Index) to a "moderate" or "minimal" impact on their daily function versus the control group. The subjects also reported better improvement in the Global Assessment of Functioning, Clinician Global Impression of Change, Pittsburgh Sleep Quality Index, and short-form McGill Pain Questionnaire, compared to traditional SCS subjects. The 10 kHz SCS subjects also reported far higher rates of both driving and sleeping with their device turned on, as well as reduced reliance on their programmers to adjust therapy settings. CONCLUSIONS: In addition to superior pain relief, 10 kHz SCS provides long-term improvements in quality of life and functionality for subjects with chronic low-back and leg pain. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01609972).

Angelman syndrome imprinting center encodes a transcriptional promoter.

Clusters of imprinted genes are often controlled by an imprinting center that is necessary for allele-specific gene expression and to reprogram parent-of-origin information between generations. An imprinted domain at 15q11-q13 is responsible for both Angelman syndrome (AS) and Prader-Willi syndrome (PWS), two clinically distinct neurodevelopmental disorders. Angelman syndrome arises from the lack of maternal contribution from the locus, whereas Prader-Willi syndrome results from the absence of paternally expressed genes. In some rare cases of PWS and AS, small deletions may lead to incorrect parent-of-origin allele identity. DNA sequences common to these deletions define a bipartite imprinting center for the AS-PWS locus. The PWS-smallest region of deletion overlap (SRO) element of the imprinting center activates expression of genes from the paternal allele. The AS-SRO element generates maternal allele identity by epigenetically inactivating the PWS-SRO in oocytes so that paternal genes are silenced on the future maternal allele. Here we have investigated functional activities of the AS-SRO, the element necessary for maternal allele identity. We find that, in humans, the AS-SRO is an oocyte-specific promoter that generates transcripts that transit the PWS-SRO. Similar upstream promoters were detected in bovine oocytes. This result is consistent with a model in which imprinting centers become DNA methylated and acquire maternal allele identity in oocytes in response to transiting transcription.

Nrf2 Expressions Correlate with WHO Grades in Gliomas and Meningiomas.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as Nrf2) is associated with cellular progression and chemotherapeutic resistance in some human cancers. We tested the relationship between Nrf2 expression and survival of patients with primary brain tumors (PBTs). METHODS: In order to realize Nrf2 protein expression in gliomas, Western blot analysis was performed in normal brain tissue and U87MG, LN229, GBM8401 and U118MG glioma cell lines protein lysates. Then, U87MG, LN229, and GBM8401 mRNA were applied to performed quantitative RT-PCR for detect Nrf2 gene expression in glioma cell lines. At last, immunohistochemical analysis was used to determine the expression of Nrf2 in samples from 178 PBTs and 10 non-neoplastic brain tissues. RESULTS: In these included in vitro studies, both Nrf2 protein and mRNA expression in all human glioma cell lines were higher than normal brain tissue. Similarly, on the viewpoint of immunohistochemistry, Nrf2 expression in gliomas were positively correlated with World Health Organization (WHO) grades. Additionally, compared with the expression of Nrf2 in non-neoplastic brain tissue, expression in meningiomas was of a stronger intensity and was present in a higher percentage of cells. Furthermore, scores were significantly higher in WHO grade II than in WHO grade I meningiomas. Finally, overall survival tended to be shorter in patients whose PBTs had higher expression of Nrf2, although the correlation was not statistically significant. CONCLUSIONS: Nrf2 overexpression positively correlated with WHO grade in gliomas and meningiomas. On the other hand, Nrf2 immunohistochemical stain could help pathologists to differentiate atypical meningiomas from benign tumors. Therefore, Nrf2 expression may be a useful biomarker to predict WHO grade and cellular behavior of PBTs.

Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial.

BACKGROUND: Current treatments for chronic pain have limited effectiveness and commonly known side effects. Given the prevalence and burden of intractable pain, additional therapeutic approaches are desired. Spinal cord stimulation (SCS) delivered at 10 kHz (as in HF10 therapy) may provide pain relief without the paresthesias typical of traditional low-frequency SCS. The objective of this randomized, parallel-arm, noninferiority study was to compare long-term safety and efficacy of SCS therapies in patients with back and leg pain. METHODS: A total of 198 subjects with both back and leg pain were randomized in a 1:1 ratio to a treatment group across 10 comprehensive pain treatment centers. Of these, 171 passed a temporary trial and were implanted with an SCS system. Responders (the primary outcome) were defined as having 50% or greater back pain reduction with no stimulation-related neurological deficit. RESULTS: At 3 months, 84.5% of implanted HF10 therapy subjects were responders for back pain and 83.1% for leg pain, and 43.8% of traditional SCS subjects were responders for back pain and 55.5% for leg pain (P < 0.001 for both back and leg pain comparisons). The relative ratio for responders was 1.9 (95% CI, 1.4 to 2.5) for back pain and 1.5 (95% CI, 1.2 to 1.9) for leg pain. The superiority of HF10 therapy over traditional SCS for leg and back pain was sustained through 12 months (P < 0.001). HF10 therapy subjects did not experience paresthesias. CONCLUSION: HF10 therapy promises to substantially impact the management of back and leg pain with broad applicability to patients, physicians, and payers.

Fluorinated photoreduced graphene oxide with semi-ionic C-F bonds: An effective carbon based photocatalyst for the removal of volatile organic compounds.

There is much interest in developing metal-free halogenated graphene such as fluorinated graphene for various catalytic applications. In this work, a fluorine-doped graphene oxide photocatalyst was investigated for photocatalytic oxidation (PCO) of a volatile organic compound (VOC), namely gaseous methanol. The fluorination process of graphene oxide (GO) was carried out via a novel and facile solution-based photoirradiation method. The fluorine atoms were doped on the surface of the GO in a semi-ionic C-F bond configuration. This presence of the semi-ionic C-F bonds induced a dramatic 7-fold increment of the hole charge carrier density of the photocatalyst. The fluorinated GO photocatalyst exhibited excellent photodegradation up to 93.5% or 0.493 h-1 according pseudo-first order kinetics for methanol. In addition, 91.7% of methanol was mineralized into harmless carbon dioxide (CO2) under UV-A irradiation. Furthermore, the photocatalyst demonstrated good stability in five cycles of methanol PCO. Besides methanol, other VOCs such as acetone and formaldehyde were also photodegraded. This work reveals the potential of fluorination in producing effective graphene-based photocatalyst for VOC removal.

Electronic Structure of Mg-, Si-, and Zn-Doped SnO2 Nanowires: Predictions from First Principles.

We investigated the electronic structure of Mg-, Si-, and Zn-doped four-faceted [001]- and [110]-oriented SnO2 nanowires using first-principles calculations based on the linear combination of atomic orbitals (LCAO) method. This approach, employing atomic-centered Gaussian-type functions as a basis set, was combined with hybrid density functional theory (DFT). Our results show qualitative agreement in predicting the formation of stable point defects due to atom substitutions on the surface of the SnO2 nanowire. Doping induces substantial atomic relaxation in the nanowires, changes in the covalency of the dopant-oxygen bond, and additional charge redistribution between the dopant and nanowire. Furthermore, our calculations reveal a narrowing of the band gap resulting from the emergence of midgap states induced by the incorporated defects. This study provides insights into the altered electronic properties caused by Mg, Si, and Zn doping, contributing to the further design of SnO2 nanowires for advanced electronic, optoelectronic, photovoltaic, and photocatalytic applications.

A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center.

The human chromosomal 15q11-15q13 region is subject to both maternal and paternal genomic imprinting. Absence of paternal gene expression from this region results in Prader-Willi syndrome (PWS), while absence of maternal gene expression leads to Angelman syndrome. Transcription of paternally expressed genes in the region depends upon an imprinting center termed the PWS-IC. Imprinting defects in PWS can be caused by microdeletions and the smallest commonly deleted region indicates that the PWS-IC lies within a region of 4.3 kb. The function and location of the PWS-IC is evolutionarily conserved, but delineation of the PWS-IC in mouse has proven difficult. The first targeted mutation of the PWS-IC, a deletion of 35 kb spanning Snrpn exon 1, exhibited a complete PWS-IC deletion phenotype. Pups inheriting this mutation paternally showed a complete loss of paternal gene expression and died neonatally. A reported deletion of 4.8 kb showed only a reduction in paternal gene expression and incomplete penetrance of neonatal lethality, suggesting that some PWS-IC function had been retained. Here, we report that a 6 kb deletion spanning Snrpn exon 1 exhibits a complete PWS-IC deletion phenotype. Pups inheriting this mutation paternally lack detectable expression of all PWS genes and paternal silencing of Ube3a, exhibit maternal DNA methylation imprints at Ndn and Mkrn3 and suffer failure to thrive leading to a fully penetrant neonatal lethality.

Imaging features of carcinoid tumors of the gastrointestinal tract.

OBJECTIVE: Recent studies have provided a better understanding of the biologic behavior of gastrointestinal carcinoid tumors. This article focusing on imaging of gastrointestinal carcinoids will emphasize epidemiology, molecular biology, taxonomy, histopathology, and management. CONCLUSION: Gastrointestinal carcinoids are a biologically heterogeneous group of tumors, with variable clinical presentation and biologic behavior. Imaging can play an important role in multidisciplinary identification and management of this disease.

Coexpression-based clustering of Arabidopsis root genes predicts functional modules in early phosphate deficiency signaling.

Phosphate (Pi) deficiency triggers the differential expression of a large set of genes, which communally adapt the plant to low Pi bioavailability. To infer functional modules in early transcriptional responses to Pi deficiency, we conducted time-course microarray experiments and subsequent coexpression-based clustering of Pi-responsive genes by pairwise comparison of genes against a customized database. Three major clusters, enriched in genes putatively functioning in transcriptional regulation, root hair formation, and developmental adaptations, were predicted from this analysis. Validation of gene expression by quantitative reverse transcription-PCR revealed that transcripts from randomly selected genes were robustly induced within the first hour after transfer to Pi-deplete medium. Pectin-related processes were among the earliest and most robust responses to Pi deficiency, indicating that cell wall alterations are critical in the early transcriptional response to Pi deficiency. Phenotypical analysis of homozygous mutants defective in the expression of genes from the root hair cluster revealed eight novel genes involved in Pi deficiency-induced root hair elongation. The plants responded rapidly to Pi deficiency by the induction of a subset of transcription factors, followed by a repression of genes involved in cell wall alterations. The combined results provide a novel, integrated view at a systems level of the root responses that acclimate Arabidopsis (Arabidopsis thaliana) to suboptimal Pi levels.