Theoretical Investigation of the Adsorbate and Potential-Induced Stability of Cu Facets During Electrochemical CO2 and CO Reduction.

The activity and product selectivity of electrocatalysts for reactions like the carbon dioxide reduction reaction (CO2RR) are intimately dependent on the catalyst's structure and composition. While engineering catalytic surfaces can improve performance, discovering the key sets of rational design principles remains challenging due to limitations in modeling catalyst stability under operating conditions. Herein, we perform first-principles density functional calculations adopting implicit solvation methods with potential control to study the influence of adsorbates and applied potential on the stability of different facets of model Cu electrocatalysts. Using coverage dependencies extracted from microkinetic models, we describe an approach for calculating potential and adsorbate-dependent contributions to surface energies under reaction conditions, where Wulff constructions are used to understand the morphological evolution of Cu electrocatalysts under CO2RR conditions. We identify that CO*, a key reaction intermediate, exhibits higher kinetically and thermodynamically accessible coverages on (100) relative to (111) facets, which can translate into an increased relative stabilization of the (100) facet during CO2RR. Our results support the known tendency for increased (111) faceting of Cu nanoparticles under more reducing conditions and that the relative increase in (100) faceting observed under CO2RR conditions is likely attributed to differences in CO* coverage between these facets.

Prosthetic Hip Dislocations in Direct Anterior Versus Posterior Approach in Patients With Instrumented Lumbar Fusion.

BACKGROUND: Instrumented posterior lumbar spinal fusion (IPLSF) has been demonstrated to contribute to instability following total hip arthroplasty (THA). It is unclear whether a supine direct anterior (DA) approach reduces the risk of instability. METHODS: A retrospective review of 1,773 patients who underwent THA through either a DA approach or a posterior approach at our institution over a 7-year period was performed. Radiographic and chart reviews were then used to identify our primary group of interest comprised of 111 patients with previous IPLSF. Radiographic review, chart review, and phone survey was performed. Dislocation rates in each approach group were then compared within this cohort of patients with IPLSF. RESULTS: Within the group of patients with IPLSF, 33.3% (n = 37) received a DA approach while 66.6% (n = 74) received a posterior approach. None of the 9 total dislocations in the DA group had IPLSF, whereas 4 of the 16 total dislocations in the posterior approach group had IPLSF (P = .78). When examining the larger group of patients, including those without IPLSF, patients undergoing a DA approach had a lower BMI and were likely have a smaller head size implanted (P < .001 for both). Using Fischer's exact test, fusion was associated with dislocation in the posterior approach group (P < .01), whereas fusion was not associated with dislocation in the anterior approach group (P = 1.0). CONCLUSIONS: While there was no significant difference in dislocation rates between posterior and anterior approach groups, in patients with IPLSF, the anterior approach had a lower percentage of dislocation events compared to the posterior approach.

Electron Optics and Valley Hall Effect of Undulated Graphene.

Electron optics is the systematic use of electromagnetic (EM) fields to control electron motions. In graphene, strain induces pseudo-electromagnetic fields to guide electron motion. Here we demonstrate the use of substrate topography to impart desirable strain on graphene to induce static pseudo-EM fields. We derive the quasi-classical equation of motion for Dirac Fermions in a pseudo-EM field in graphene and establish the correspondence between the quasi-classical and quantum mechanical snake states. Based on the trajectory analysis, we design sculpted substrates to realize various "optical devices" such as a converging lens or a collimator, and further propose a setup to achieve valley Hall effect solely through substrate patterning, without any external fields, to be used in valleytronics applications. Finally, we discuss how the predicted strain/pseudo-EM field patterns can be experimentally sustained by typical substrates and generalized to other 2D materials.

Pharmacological Characterization of Low Molecular Weight Biased Agonists at the Follicle Stimulating Hormone Receptor.

Follicle-stimulating hormone receptor (FSHR) plays a key role in reproduction through the activation of multiple signaling pathways. Low molecular weight (LMW) ligands composed of biased agonist properties are highly valuable tools to decipher complex signaling mechanisms as they allow selective activation of discrete signaling cascades. However, available LMW FSHR ligands have not been fully characterized yet. In this context, we explored the pharmacological diversity of three benzamide and two thiazolidinone derivatives compared to FSH. Concentration/activity curves were generated for Gαs, Gαq, Gαi, ß-arrestin 2 recruitment, and cAMP production, using BRET assays in living cells. ERK phosphorylation was analyzed by Western blotting, and CRE-dependent transcription was assessed using a luciferase reporter assay. All assays were done in either wild-type, Gαs or ß-arrestin 1/2 CRISPR knockout HEK293 cells. Bias factors were calculated for each pair of read-outs by using the operational model. Our results show that each ligand presented a discrete pharmacological efficacy compared to FSH, ranging from super-agonist for ß-arrestin 2 recruitment to pure Gαs bias. Interestingly, LMW ligands generated kinetic profiles distinct from FSH (i.e., faster, slower or transient, depending on the ligand) and correlated with CRE-dependent transcription. In addition, clear system biases were observed in cells depleted of either Gαs or ß-arrestin genes. Such LMW properties are useful pharmacological tools to better dissect the multiple signaling pathways activated by FSHR and assess their relative contributions at the cellular and physio-pathological levels.

A Laboratory Study on Effects of Cycling Helmet Fit on Biomechanical Measures Associated With Head and Neck Injury and Dynamic Helmet Retention.

There is a scant biomechanical literature that tests, in a laboratory setting, whether or not determinants of helmet fit affect biomechanical parameters associated with injury. Using conventional cycling helmets and repeatable models of the human head and neck, integrated into a guided drop impact experiment at speeds up to 6 m/s, this study tests the hypothesis that fit affects head kinematics, neck kinetics, and the extent to which the helmet moves relative to the underlying head (an indicator of helmet positional stability). While there were a small subset of cases where head kinematics were statistically significantly altered by fit, when viewed as a whole our measures of head kinematics suggest that fit does not systematically alter kinematics of the head secondary to impact. Similarly, when viewed as a whole, our data suggest that fit does not systematically alter resultant neck compression and resultant moment and associated biomechanical measures. Our data suggest that backward fit helmets exhibit the worst dynamic stability, in particular when the torso is impacted before the helmeted head is impacted, suggesting that the typical certification method of dynamical loading of a helmet to quantify retention may not be representative of highly plausible cycling incident scenarios where impact forces are first applied to the torso leading to loading of the neck prior to the head. Further study is warranted so that factors of fit that affect injury outcome are uncovered in both laboratory and real-world settings.

Heightened amygdala responsiveness in s-carriers of 5-HTTLPR genetic polymorphism reflects enhanced cortical rather than subcortical inputs: An MEG study.

Short allele carriers (S-carriers) of the serotonin transporter gene (5-HTTLPR) show an elevated amygdala response to emotional stimuli relative to long allele carriers (LL-homozygous). However, whether this reflects increased responsiveness of the amygdala generally or interactions between the amygdala and the specific input systems remains unknown. It is argued that the amygdala receives input via a quick subcortical and a slower cortical pathway. If the elevated amygdala response in S-carriers reflects generally increased amygdala responding, then group differences in amygdala should be seen across the amygdala response time course. However, if the difference is a secondary consequence of enhanced amygdala-cortical interactions, then group differences might only be present later in the amygdala response. Using magnetoencephalography (MEG), we found an enhanced amygdala response to fearful expressions starting 40-50 ms poststimulus. However, group differences in the amygdala were only seen 190-200 ms poststimulus, preceded by increased superior temporal sulcus (STS) responses in S-carriers from 130 to 140 ms poststimulus. An enhanced amygdala response to angry expressions started 260-270 ms poststimulus with group differences in the amygdala starting at 160-170 ms poststimulus onset, preceded by increased STS responses in S-carriers from 150 to 160 ms poststimulus. These suggest that enhanced amygdala responses in S-carriers might reflect enhanced STS-amygdala connectivity in S-carriers. Hum Brain Mapp 38:4313-4321, 2017. © 2017 Wiley Periodicals, Inc.

Refuting the lipstick sign.

BACKGROUND: Arthroscopic examination of the tendon has been described as the "gold standard" for diagnosis of tendinitis of the long head of the biceps (LHB). An arthroscopic finding of an inflamed and hyperemic LHB within the bicipital groove has been described as the "lipstick sign." Studies evaluating direct visualization in diagnosis of LHB tendinitis are lacking. METHODS: During a 1-year period, 363 arthroscopic shoulder procedures were performed, with 16 and 39 patients prospectively selected as positive cases and negative controls, respectively. All positive controls had groove tenderness, positive Speed maneuver, and diagnostic ultrasound-guided bicipital injection. Negative controls had none of these findings. Six surgeons reviewed randomized deidentified arthroscopic pictures of enrolled patients The surgeons were asked whether the images demonstrated LHB tendinitis and if the lipstick sign was present. RESULTS: Overall sensitivity and specificity were 49% and 66%, respectively, for detecting LHB tendinitis and 64% and 31%, respectively, for erythema. The nonweighted κ score for interobserver reliability ranged from 0.042 to 0.419 (mean, 0.215 ± 0.116) for tendinitis and from 0.486 to 0.835 (mean, 0.680 ± 0.102) for erythema. The nonweighted κ score for intraobserver reliability ranged from 0.264 to 0.854 (mean, 0.615) for tendinitis and from 0.641 to 0.951 (mean, 0.783) for erythema. CONCLUSIONS: The presence of the lipstick sign performed only moderately well in a rigorously designed level III study to evaluate its sensitivity and specificity. There is only fair agreement among participating surgeons in diagnosing LHB tendinitis arthroscopically. Consequently, LHB tendinitis requiring tenodesis remains a clinical diagnosis that should be made before arthroscopic examination.

Carrier Delocalization in Two-Dimensional Coplanar p-n Junctions of Graphene and Metal Dichalcogenides.

With the lateral coplanar heterojunctions of two-dimensional monolayer materials turning into reality, the quantitative understanding of their electronic, electrostatic, doping, and scaling properties becomes imperative. In contrast to traditional bulk 3D junctions where carrier equilibrium is reached through local charge redistribution, a highly nonlocalized charge transfer (trailing off as 1/x away from the interface) is present in lateral 2D junctions, increasing the junction size considerably. The depletion width scales as p(-1), while the differential capacitance varies very little with the doping level p. The properties of lateral 2D junctions are further quantified through numerical analysis of realistic materials, with graphene, MoS2, and their hybrid serving as examples. Careful analysis of the built-in potential profile shows strong reduction of Fermi level pinning, suggesting better control of the barrier in 2D metal-semiconductor junctions.

Riemann Surfaces of Carbon as Graphene Nanosolenoids.

Traditional inductors in modern electronics consume excessive areas in the integrated circuits. Carbon nanostructures can offer efficient alternatives if the recognized high electrical conductivity of graphene can be properly organized in space to yield a current-generated magnetic field that is both strong and confined. Here we report on an extraordinary inductor nanostructure naturally occurring as a screw dislocation in graphitic carbons. Its elegant helicoid topology, resembling a Riemann surface, ensures full covalent connectivity of all graphene layers, joined in a single layer wound around the dislocation line. If voltage is applied, electrical currents flow helically and thus give rise to a very large (∼1 T at normal operational voltage) magnetic field and bring about superior (per mass or volume) inductance, both owing to unique winding density. Such a solenoid of small diameter behaves as a quantum conductor whose current distribution between the core and exterior varies with applied voltage, resulting in nonlinear inductance.

Accuracy of a Wearable Sensor for Measures of Head Kinematics and Calculation of Brain Tissue Strain.

Wearable kinematic sensors can be used to study head injury biomechanics based on kinematics and, more recently, based on tissue strain metrics using kinematics-driven brain models. These sensors require in-situ calibration and there is currently no data conveying wearable ability to estimate tissue strain. We simulated head impact (n = 871) to a 50th percentile Hybrid III (H-III) head wearing a hockey helmet instrumented with wearable GForceTracker (GFT) sensors measuring linear acceleration and angular velocity. A GFT was also fixed within the H-III head to establish a lower boundary on systematic errors. We quantified GFT errors relative to H-III measures based on peak kinematics and cumulative strain damage measure (CSDM). The smallest mean errors were 12% (peak resultant linear acceleration) and 15% (peak resultant angular velocity) for the GFT within the H-III. Errors for GFTs on the helmet were on average 54% (peak resultant linear acceleration) and 21% (peak resultant angular velocity). On average, the GFT inside the helmet overestimated CSDM by 0.15.

Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer.

Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor, is an important drug target in the development of novel therapeutics for reproductive indications. The FSHR extracellular domains were observed in the crystal structure as a trimer, which enabled us to propose a novel model for the receptor activation mechanism. The model predicts that FSHR binds Asnα(52)-deglycosylated FSH at a 3-fold higher capacity than fully glycosylated FSH. It also predicts that, upon dissociation of the FSHR trimer into monomers, the binding of glycosylated FSH, but not deglycosylated FSH, would increase 3-fold, and that the dissociated monomers would in turn enhance FSHR binding and signaling activities by 3-fold. This study presents evidence confirming these predictions and provides crystallographic and mutagenesis data supporting the proposed model. The model also provides a mechanistic explanation to the agonist and antagonist activities of thyroid-stimulating hormone receptor autoantibodies. We conclude that FSHR exists as a functional trimer.

Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor.

FSH, a glycoprotein hormone, and the FSH receptor (FSHR), a G protein-coupled receptor, play central roles in human reproduction. We report the crystal structure of FSH in complex with the entire extracellular domain of FSHR (FSHR(ED)), including the enigmatic hinge region that is responsible for signal specificity. Surprisingly, the hinge region does not form a separate structural unit as widely anticipated but is part of the integral structure of FSHR(ED). In addition to the known hormone-binding site, FSHR(ED) provides interaction sites with the hormone: a sulfotyrosine (sTyr) site in the hinge region consistent with previous studies and a potential exosite resulting from putative receptor trimerization. Our structure, in comparison to others, suggests FSHR interacts with its ligand in two steps: ligand recruitment followed by sTyr recognition. FSH first binds to the high-affinity hormone-binding subdomain of FSHR and reshapes the ligand conformation to form a sTyr-binding pocket. FSHR then inserts its sTyr (i.e., sulfated Tyr335) into the FSH nascent pocket, eventually leading to receptor activation.

Discovery of substituted benzamides as follicle stimulating hormone receptor allosteric modulators.

Follicle-stimulating hormone (FSH), acting on its receptor (FSHR), plays a pivotal role in the stimulation of follicular development and maturation. Multiple injections of protein formulations are used during clinical protocols for ovulation induction and for in vitro fertilization that are followed by a selection of assisted reproductive technologies. In order to increase patient convenience and compliance several research groups have searched for orally bioavailable FSH mimetics for innovative fertility medicines. We report here the discovery of a series of substituted benzamides as positive allosteric modulators (PAM) targeting FSHR. Optimization of this series has led to enhanced activity in primary rat granulosa cells, as well as remarkable selectivity against the closely related luteinizing hormone receptor (LHR) and thyroid stimulating hormone receptor (TSHR). Two modulators, 9j and 9k, showed promising in vitro and pharmacokinetic profiles.

Pifithrin-µ Induces Stress Granule Formation, Regulates Cell Survival, and Rewires Cellular Signaling.

(1) Background: Stress granules (SGs) are cytoplasmic protein-RNA condensates that assemble in response to various insults. SG production is driven by signaling pathways that are relevant to human disease. Compounds that modulate SG characteristics are therefore of clinical interest. Pifithrin-µ is a candidate anti-tumor agent that inhibits members of the hsp70 chaperone family. While hsp70s are required for granulostasis, the impact of pifithrin-µ on SG formation is unknown. (2) Methods: Using HeLa cells as model system, cell-based assays evaluated the effects of pifithrin-µ on cell viability. Quantitative Western blotting assessed cell signaling events and SG proteins. Confocal microscopy combined with quantitative image analyses examined multiple SG parameters. (3) Results: Pifithrin-µ induced bona fide SGs in the absence of exogenous stress. These SGs were dynamic; their properties were determined by the duration of pifithrin-µ treatment. The phosphorylation of eIF2α was mandatory to generate SGs upon pifithrin-µ exposure. Moreover, the formation of pifithrin-µ SGs was accompanied by profound changes in cell signaling. Pifithrin-µ reduced the activation of 5'-AMP-activated protein kinase, whereas the pro-survival protein kinase Akt was activated. Long-term pifithrin-µ treatment caused a marked loss of cell viability. (4) Conclusions: Our study identified stress-related changes in cellular homeostasis that are elicited by pifithrin-µ. These insights are important knowledge for the appropriate therapeutic use of pifithrin-µ and related compounds.

SC912 inhibits AR-V7 activity in castration-resistant prostate cancer by targeting the androgen receptor N-terminal domain.

Androgen deprivation therapies (ADT) are the mainstay treatments for castration-resistant prostate cancer (CRPC). ADT suppresses the androgen receptor (AR) signaling by blocking androgen biosynthesis or inhibiting AR with antiandrogens that target AR's ligand-binding domain (LBD). However, the ADT's effect is short-lived, as the AR signaling inevitably arises again, which is frequently coupled with AR-V7 overexpression. AR-V7 is a truncated form of AR that lacks the LBD, thus being constitutively active in the absence of androgens and irresponsive to AR-LBD-targeting inhibitors. Though compelling evidence has tied AR-V7 to drug resistance in CRPC, pharmacological inhibition of AR-V7 is still an unmet need. Here, we discovered a small molecule, SC912, which binds to full-length AR as well as AR-V7 through AR N-terminal domain (AR-NTD). This pan-AR targeting relies on the amino acids 507-531 in the AR-NTD. SC912 also disrupted AR-V7 transcriptional activity, impaired AR-V7 nuclear localization and DNA binding. In the AR-V7 positive CRPC cells, SC912 suppressed proliferation, induced cell-cycle arrest, and apoptosis. In the AR-V7 expressing CRPC xenografts, SC912 attenuated tumor growth and antagonized intratumoral AR signaling. Together, these results suggested the therapeutic potential of SC912 for CRPC.

Design and performance of an ultrahigh vacuum spectroscopic-imaging scanning tunneling microscope with a hybrid vibration isolation system.

A spectroscopic imaging-scanning tunneling microscope (SI-STM) allows for the atomic scale visualization of the surface electronic and magnetic structure of novel quantum materials with a high energy resolution. To achieve the optimal performance, a low vibration facility is required. Here, we describe the design and performance of an ultrahigh vacuum STM system supported by a hybrid vibration isolation system that consists of a pneumatic passive and a piezoelectric active vibration isolation stage. We present the detailed vibrational noise analysis of the hybrid vibration isolation system, which shows that the vibration level can be suppressed below 10-8 m/sec/√Hz for most frequencies up to 100 Hz. Combined with a rigid STM design, vibrational noise can be successfully removed from the tunneling current. We demonstrate the performance of our STM system by taking high resolution spectroscopic maps and topographic images on several quantum materials. Our results establish a new strategy to achieve an effective vibration isolation system for high-resolution STM and other scanning probe microscopies to investigate the nanoscale quantum phenomena.

The crosstalk between neuropilin-1 and tumor necrosis factor-α in endothelial cells.

Tumor necrosis factor-α (TNFα) is a master cytokine which induces expression of chemokines and adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), in endothelial cells to initiate the vascular inflammatory response. In this study, we identified neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, as a modulator of TNFα-induced inflammatory response of endothelial cells. NRP1 shRNA expression suppressed TNFα-stimulated leukocyte adhesion and expression of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVECs). Likewise, it reduced TNFα-induced phosphorylation of MAPK p38 but did not significantly affect other TNF-induced signaling pathways, such as the classical NFκB and the AKT pathway. Immunofluorescent staining demonstrated co-localization of NRP1 with the two receptors of TNF, TNFR1 and TNFR2. Co-immunoprecipitation further confirmed that NRP1 was in the same protein complex or membrane compartment as TNFR1 and TNFR2, respectively. Modulation of NRP1 expression, however, neither affected TNFR levels in the cell membrane nor the receptor binding affinities of TNFα. Although a direct interface between NRP1 and TNFα/TNFR1 appeared possible from a protein docking model, a direct interaction was not supported by binding assays in cell-free microplates and cultured cells. Furthermore, TNFα was shown to downregulate NRP1 in a time-dependent manner through TNFR1-NFκB pathway in HUVECs. Taken together, our study reveals a novel reciprocal crosstalk between NRP1 and TNFα in vascular endothelial cells.

Systematic Exposure in Revision Total Hip Arthroplasty: The Posterior Approach.

As indications for total hip arthroplasty (THA) continue to expand, and patients continue to live longer with more active lifestyles, the incidence of revision THA is expected to rise. General orthopaedic surgeons are now beginning to consider doing revision THA surgery because of the increased revision burden being experienced nationwide. While classical approaches to the hip can be used for simple revisions, extensile exposure techniques in conjunction with selective soft-tissue releases are often required for adequate visualization for more complex revision cases. This review provides a systematic approach to surgical exposure for revision THA using the posterior approach. The surgeon should follow a stepwise progression to obtain safe, adequate, and reproducible visualization of both the acetabulum and the proximal femur.

The Iatrogenic Injury Potential of Self-adherent Elastic Bandages in Finger Injuries.

BACKGROUND: The use of a self-adherent, elastic bandage is a practical way to dress finger injuries. Multiple reports describe iatrogenic injuries from elastic bandages, ranging from skin necrosis to finger gangrene, necessitating amputations. This study investigated whether elastic bandages can compromise digital perfusion by occluding arterial blood flow in healthy volunteers and evaluated the utility of pulse oximetry as a monitoring tool for digital perfusion. A technique for safe bandage application is proposed. METHODS: A commercially available elastic bandage was wrapped around the index finger of 20 healthy volunteers at varying degrees of stretch. Digital perfusion measurements were carried out using photoelectric pulse transduction, laser Doppler flowmetry, and pulse oximetry. Intracompartmental pressure measurements were recorded using a separate in vitro experimental model. RESULTS: Elastic bandages applied at maximum stretch did not change digital brachial index or pulse oximetry values, suggesting arterial blood flow was preserved distal to the bandage. Intracompartmental pressure measurements at maximum stretch remained below the systolic digital pressure. In contrast, superficial dermal perfusion fell to 32% of normal as measured by laser Doppler flow, at 100% bandage stretch. CONCLUSION: This study suggests a risk for iatrogenic injury when using elastic bandages for finger dressings. While arterial inflow was never compromised, pressures were high enough to occlude superficial venous outflow, which may begin at 20% bandage stretch. Pulse oximetry failed to detect changes distal to applied dressings, and we do not recommend it to detect digital vascular compromise in this setting.

Oral follicle-stimulating hormone receptor agonist affects granulosa cells differently than recombinant human FSH.

OBJECTIVE: To determine whether TOP5300, a novel oral follicle-stimulating hormone (FSH) receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from patients undergoing in vitro fertilization. DESIGN: Basic science research with a preclinical allosteric FSHR agonist. SETTING: University hospital. PATIENT(S): Patients with infertility at a single academic fertility clinic were recruited under an Institutional Review Board-approved protocol. Primary granulosa cell cultures were established for 41 patients, of whom 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovary syndrome (PCOS), and 4 had a combination of diagnoses, such as ARA and PCOS. INTERVENTION(S): Primary granulosa-lutein (GL) cell cultures were treated with rh-FSH, TOP5300, or vehicle. MAIN OUTCOME MEASURE(S): Estradiol (E2) production using enzyme-linked immunosorbent assay, steroid pathway gene expression of StAR and aromatase using quantitative polymerase chain reaction, and FSHR membrane localization using immunofluorescence were measured in human GL cells. RESULT(S): TOP5300 consistently stimulated E2 production among patients with NOR, ARA, and PCOS. Recombinant FSH was the more potent ligand in GL cells from patients with NOR but was ineffective in cells from patients with ARA or PCOS. The lowest level of FSHR plasma membrane localization was seen in patients with ARA, although FSHR localization was more abundant in cells from patients with PCOS; the highest levels were present in cells from patients with NOR. The localization of FSHR was not affected by TOP5300 relative to rh-FSH in any patient group. TOP5300 stimulated greater expression of StAR and CYP19A1 across cells from all patients with NOR, ARA, and PCOS combined, although rh-FSH was unable to stimulate StAR and aromatase (CYP19A1) expression in cells from patients with PCOS. TOP5300-induced expression of StAR and CYP19A1 mRNA among patients with ARA and NOR was consistently lower than that observed in cells from patients with PCOS. CONCLUSION(S): TOP5300 appears to stimulate E2 production and steroidogenic gene expression from GL cells more than rh-FSH in PCOS, relative to patients with ARA and NOR. It does not appear that localization of FSHR at cell membranes is a limiting step for TOP5300 or rh-FSH stimulation of steroidogenic gene expression and E2 production.