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Characterizing the structural ensembles of intrinsically disordered proteins (IDPs) is essential for studying structure-function relationships as conformational dynamics govern proteins’ biological functions. Due to the notable difference between the neutron scattering lengths of hydrogen and deuterium, selective labeling and contrast matching in small-angle neutron scattering (SANS) becomes an effective tool to study dynamic structures of disordered systems. However, the experimental timescale typically results in measurements averaged over multiple conformations, leaving complex SANS data for disentanglement. We hereby demonstrate an integrated method to elucidate the structural ensemble of a protein complex formed by two IDP domains, the NCBD/ACTR complex, using data from selective labeling SANS experiments, microsecond all-atom molecular dynamics (MD) simulations with four molecular mechanics force fields, and an autoencoder-based deep learning (DL) algorithm. By incorporating structural metrics derived from the SANS experiments as constraints in MD structure classification, we describe a structural ensemble that captures the experimental SANS and, in addition, NMR data better than MD ensembles generated by one single force field. Based on structural similarity, DL reveals three clusters of distinct conformations in the ensemble. Our results demonstrate a new integrated approach for characterizing structural ensembles of IDPs.

Antigen-specific immunotherapies (ASI) require successful loading and presentation of antigen peptides into the major histocompatibility complex (MHC) binding cleft. One route of ASI design is to mutate native antigens for either stronger or weaker binding interaction to MHC. Exploring all possible mutations is costly both experimentally and computationally. To reduce experimental and computational expense, here we investigate the minimal amount of prior data required to accurately predict the relative binding affinity of point mutations for peptide-MHC class II (pMHCII) binding. Using data from different residue subsets, we interpolate pMHCII mutant binding affinities by Gaussian process (GP) regression of residue volume and hydrophobicity. We apply GP regression to an experimental data set from the Immune Epitope Database, and theoretical data sets from NetMHCIIpan and Free Energy Perturbation calculations. We find that GP regression can predict binding affinities of nine neutral residues from a six-residue subset with an average R2 coefficient of determination value of 0.62 ± 0.04 (±95% CI), average error of 0.09 ± 0.01 kcal/mol (±95% CI), and with an receiver operating characteristic (ROC) AUC value of 0.92 for binary classification of enhanced or diminished binding affinity. Similarly, metrics increase to an R2 value of 0.69 ± 0.04, average error of 0.07 ± 0.01 kcal/mol, and an ROC AUC value of 0.94 for predicting seven neutral residues from an eight-residue subset. Our work finds that prediction is most accurate for neutral residues at anchor residue sites without register shift. This work holds relevance to predicting pMHCII binding and accelerating ASI design.

Despite the remarkable electrochemical properties of graphene, strong van der Waals attraction between graphene and biomolecules often causes cytotoxicity, which hinders its applications in the biomedical field. Unfortunately, surface passivation of graphene might stimulate undesired immune response as the nanomaterial triggers cytokine production through membrane receptor activation. Herein, we use all-atom Molecular Dynamics (MD) simulations to unravel the underlying mechanism of graphene-induced inside-out activation of integrin αvβ8, a prominent membrane receptor expressed in immune cells. We model the transmembrane (TM) domains of integrin αvβ8 in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer and observe the structural changes in the integrin–membrane complex when interacting with a graphene nanosheet across the membrane. We find that the β8 TM domain interacts with the graphene nanosheet directly or indirectly through extracted lipids, facilitating the pulling of a β8 subunit away from an αv subunit and thus leading to the disruption of the TM domain association by breaking the hydrophobic cluster in the cytoplasmic domains of the αv and β8 subunits. Alanine substitution of two conserved phenylalanine residues on the αv subunit at this hydrophobic cluster further reveals the importance of a stable T-shaped structure in retaining integrin in its inactive state. Our results agree with previous studies on the interactions between other integrin subtypes and their endogenous activators, suggesting an intriguing role that the graphene nanosheet may play in the integrin-related signal transduction during its interaction with the membrane.

Phosphorene, a monolayer of black phosphorus, has emerged as one of the most promising two-dimensional (2D) nanomaterials for various applications in the post-graphene-discovery period due to its highly anisotropic structure and novel properties. In order to apply phosphorene in biomedical fields, it is crucial to understand how it interacts with biomolecules. Herein, we use both molecular dynamics (MD) simulations and experimental techniques to investigate the interactions of phosphorene with a dsDNA segment. Our results reveal that dsDNA can form a stable binding on the phosphorene surface through the terminal base pairs and adopt an upright orientation regardless of its initial configurations. Moreover, the binding strength of dsDNA with phosphorene is found to be mild and does not cause significant distortion in the internal structure of dsDNA. This phenomenon is attributed to the weaker dispersion interaction between dsDNA and phosphorene. Further analysis of the free energy profile calculated by the umbrella sampling technique suggests that the puckered surface morphology significantly reduces the adsorption free energy of DNA bases to phosphorene. Compared to graphene, phosphorene is found to show a milder attraction to DNA, which is confirmed by our electrophoresis experiments. We believe that these findings provide valuable insight into the molecular interactions between phosphorene and dsDNA which may prompt further investigation of phosphorene for future biomedical applications.

Agent-based modeling (ABM) is a powerful simulation technique which describes a complex dynamic system based on its interacting constituent entities. While the flexibility of ABM enables broad application, the complexity of real-world models demands intensive computing resources and computational time; however, a metamodel may be constructed to gain insight at less computational expense. Here, we developed a model in NetLogo to describe the growth of a microbial population consisting of Pantoea. We applied 13 parameters that defined the model and actively changed seven of the parameters to modulate the evolution of the population curve in response to these changes. We efficiently performed more than 3,000 simulations using a Python wrapper, NL4Py. Upon evaluation of the correlation between the active parameters and outputs by random forest regression, we found that the parameters which define the depth of medium and glucose concentration affect the population curves significantly. Subsequently, we constructed a metamodel, a dense neural network, to predict the simulation outputs from the active parameters and found that it achieves high prediction accuracy, reaching an R2 coefficient of determination value up to 0.92. Our approach of using a combination of ABM with random forest regression and neural network reduces the number of required ABM simulations. The simplified and refined metamodels may provide insights into the complex dynamic system before their transition to more sophisticated models that run on high-performance computing systems. The ultimate goal is to build a bridge between simulation and experiment, allowing model validation by comparing the simulated data to experimental data in microbiology.

Abnormal peptide assembly and aggregation is associated with an array of neurodegenerative diseases including Alzheimer's disease (AD). A detailed understanding of how nanostructured materials such as oxidized graphene perturb the peptide assembly and subsequently induce fibril dissociation may open new directions for the development of potential AD treatments. Here, we investigate the impact of surface inhomogeneity of graphene oxide (GO) on the assembly of amyloid-beta Aβ16-21 peptides on GO surfaces with different degrees of oxidation using molecular dynamics simulations. Interestingly, nonuniform GO nanosheets (in terms of oxidation sites) have a much stronger perturbation effect on the structure of Aβ16-21 assembly. The Aβ peptides exhibit a remarkable tendency in binding to the scattered interfaces between unoxidized and oxidized regions, which induces the dissociation of Aβ amyloid fibril. These findings should deepen our understanding of surface-induced peptide dissociation and stimulate discovery of alternative AD treatments.

Physician burnout has been on the rise over the last several decades in a variety of specialties, leading to high rates of physician suicide and poor health outcomes for patients. As leaders in healthcare attempt to combat this issue through mental health initiatives and changes in medical training policies, we propose patient advocacy as a powerful technique to combat physician burnout and restore autonomy, purpose, and meaning into physicians' lives.

When nanoparticles interact with cellular or organelle membranes, the coating ligands are known to affect the integrity of the membranes, which regulate cell death and inflammation. However, the molecular mechanisms of this modulation remain unresolved. Here, we use synchrotron X-ray liquid surface scattering and molecular dynamics simulations to study interface structures between phospholipids and gold nanorods (AuNRs) coated by surfactant and polyelectrolyte. These ligands are two types of widely used surface modification with different self-assembled structures and stabilities on the surface of nanoparticles. We reveal distinct mechanisms of the ligand stability in disrupting membrane integrity. We find that the cationic surfactant ligand cetyltrimethylammonium bromide detaches from the AuNRs and inserts into phospholipids, resulting in reduced membrane thickness by compressing the phospholipids to align with the shorter ligand. Conversely, the cationic polyelectrolyte ligand poly(diallyldimethylammonium chloride) is more stable on AuNRs; although it adsorbs onto the membrane, it does not cause much impairment. The distinct coating ligand interactions with phospholipids are further verified by cellular responses including impaired lysosomal membranes and triggered inflammatory effects in macrophages. Together, the quantitative analysis of interface structures elucidates key bio-nano interactions and highlights the importance of surface ligand stability for safety and rational design of nanoparticles.

Structural defects in nanomaterials can alter their physical and chemical properties including magnetization, electronic and thermal conductivities, light absorption, and emission capabilities. Here, we investigated the potential impact of these defects on their biological effects through molecular dynamics simulations. By modeling the interaction between a graphene nanosheet and a widely used model protein, the chicken villin headpiece subdomain (HP35), we observed severe protein denaturation upon contact with defective graphene, while the protein remained intact on ideal graphene. The enhanced toxicity of defective graphene was due to the stronger attraction of the surface residues of HP35 from the defect edges (represented by carboxyl groups in our simulations) than from the ideal graphene. Upon binding to defective graphene, the contacting residues were restrained near the defective sites, which acted as "anchors" for the adsorbed protein. The "anchors" subsequently caused the protein to expose its aromatic and hydrophobic core residues to the graphene surface, via strong π-π stacking and hydrophobic interactions, thus leading to the unfolding of the protein. These findings not only highlight the importance of defects in nanomaterials' impact on biological systems, but also provide insights into fine-tuning the potential biological properties of nanomaterials through defect engineering.

A recent phenomenal study discovered that the extension domain of secreted amyloid-β precursor protein (sAPP) can bind to the intrinsically disordered sushi 1 domain of the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a) and modulate its synaptic transmission. The work provided an important structural foundation for the modulation of GABABR1a; however, the detailed molecular interaction mechanism, crucial for future drug design, remains elusive. Here, we further investigated the dynamical interactions between sAPP peptides and the natively unstructured sushi 1 domain using all-atom molecular dynamics simulations, for both the 17-residue sAPP peptide (APP 17-mer) and its minimally active 9 residue segment (APP 9-mer). We then explored mutations of the APP 9-mer with rigorous free energy perturbation (FEP) calculations. Our in silico mutagenesis studies revealed key residues (D4, W6, and W7) responsible for the binding with the sushi 1 domain. More importantly, one double mutation based on different vertebrate APP sequences from evolution exhibited a stronger binding (ΔΔG = −1.91 ± 0.66 kcal mol−1), indicating a potentially enhanced GABABR1a modulator. These large-scale simulations may provide new insights into the binding mechanism between sAPP and the sushi 1 domain, which could open new avenues in the development of future GABABR1a-specific therapeutics., A recent phenomenal study discovered that the extension domain of secreted amyloid-β precursor protein (sAPP) can bind to the intrinsically disordered sushi 1 domain of the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a) and modulate its synaptic transmission.

Antigen-specific immunotherapies (ASI) require successful loading and presentation of antigen peptide into the major histocompatibility complex (MHC) binding cleft. One route of ASI design is to mutate native antigens for either stronger or weaker binding interaction to MHC. Exploring all possible mutations is costly both experimentally and computationally. To reduce experimental and computational expense, here we investigate the minimal amount of prior data required to accurately predict the relative binding affinity of point mutations for peptide-MHC class II (pMHCII) binding. Using data from different residue subsets, we interpolate pMHCII mutant binding affinities by Gaussian process (GP) regression of residue volume and hydrophobicity. We apply GP regression to an experimental dataset from the Immune Epitope Database, and theoretical datasets from NetMHCIIpan and Free Energy Perturbation calculations. We find that GP regression can predict binding affinities of 9 neutral residues from a 6-residue subset with an average R2 coefficient of determination value of 0.62 ± 0.04 (±95% CI), average error of 0.09 ± 0.01 kcal/mol (±95% CI), and with an ROC AUC value of 0.92 for binary classification of enhanced or diminished binding affinity. Similarly, metrics increase to an R2 value of 0.69 ± 0.04, average error of 0.07 ± 0.01 kcal/mol, and an ROC AUC value of 0.94 for predicting 7 neutral residues from an 8-residue subset. Our work finds that prediction is most accurate for neutral residues at anchor residue sites without register shift. This work holds relevance to predicting pMHCII binding and accelerating ASI design.

Glycosylation of secondary metabolites involves plant UDP-dependent glycosyltransferases (UGTs). UGTs have shown promise as catalysts in the synthesis of glycosides for medical treatment. However, limited understanding at the molecular level due to insufficient biochemical and structural information has hindered potential applications of most of these UGTs. In the absence of experimental crystal structures, we employed advanced molecular modelling and simulations in conjunction with biochemical characterisation to design a workflow to study five Group H Arabidopsis thaliana (76E1, 76E2, 76E4, 76E5, 76D1) UGTs. Based on our rational structural manipulation and analysis, we identified key amino acids (P129 in 76D1; D374 in 76E2; K275 in 76E4), which when mutated improved donor-substrate recognition than wildtype UGTs. Molecular dynamics simulations and deep learning analysis identified structural differences, which drive substrate preferences. The design of these UGTs with broader substrate specificity may play important role in biotechnological and industrial applications. These findings can also serve as basis to study other plant UGTs and thereby advancing UGT enzyme engineering. Federal Scholarship Board/Presidential Special Scholarship Scheme for Innovation and Development (PRESSID), Nigeria; Sichuan Science and Technology Program

Unlike most matrix metalloproteinase (MMP) inhibitors, which target the conserved catalytic zinc site, Gd@C82(OH)22 indirectly inhibits MMP-9 activity by binding at the ligand specificity S1' loop. The allosteric binding makes Gd@C82(OH)22 a promising inhibitor selective for MMP-9. However, the hydrophobic nature of the aromatic carbon cage may cause Gd@C82(OH)22 to self-aggregate in aqueous solutions, hence weakening the binding. In this study, we designed Gd@C82(OH)22 derivatives aiming at improving the binding affinity for MMP-9. Upon a mutation that substitutes a new functional group (-PO42-, -CH2CO2-, -CO2-, -NH3+, or -CONH2) for a hydroxyl group on the fullerenol surface, we calculated the changes in the binding free energy to the catalytic domain of human MMP-9 using the free energy perturbation (FEP) method. We found that the higher the net charge of the functional group, the stronger the binding. Compared with Gd@C82(OH)22, Gd@C82(OH)21(PO4)2- binds at least 1.5 to 2.5 kcal mol-1 more strongly to MMP-9. The binding is specifically controlled by electrostatic interactions between the phosphate group and the charged residues at the binding site. In addition to the net charge, the binding free energy can be delicately adjusted by other factors, such as the functionalization site on Gd@C82(OH)22, the local environment of the putative binding site of MMP-9, and the presence of ions near the charged functional group. The results of our study shed light on the potential of developing Gd@C82(OH)22 derivatives as nanodrugs for treating the pathological diseases associated with unregulated MMP-9 activity.

Background: Hysteroscopic morcellation removes uterine pathology under direct visualization with continuous real-time tissue fragment removal. Objective: The aim of this study was to explore the feasibility of hysteroscopic morcellation across a diverse set of facilities, including both surgical and office-based settings. Design: This was a prospective, single-arm, multicenter registry development (Canadian Task Force classification II-3). Materials and Methods: Thirty-four U.S. obstetrics and gynecology facilities enrolled subjects into the registry. Inclusion criteria were women ages 18–65 with indications for hysteroscopic myomectomy and/or polypectomy who were treated with the MyoSure® Hysteroscopic Tissue Removal System (Hologic Inc., Marlborough, MA). Intrauterine lesion type/size and removal parameters, adverse events (AEs), and physician satisfaction ratings were recorded. Results: A total of 559 pathologies (187 fibroids; 372 polyps) were removed from 278 registered subjects (mean age: 43.9 ± 9.0 years), with 250 procedures (89.9%) performed in an ambulatory surgery center or hospital outpatient setting and 28 (10.1%) in a gynecologic office setting. Most patients (n = 206, 74.1%) were treated for abnormal uterine bleeding, and 42 (15.1%) were treated for infertility. Mean fibroid diameter was 2.2 ± 1.2 cm. Mean polyp diameter was 1.3 ± 1.0 cm. Overall mean percentage of pathology removed was 95.4% (polyps 99.3%, fibroids 86.8%). Five AEs included four incidents of blunt cervical trauma and a single postoperative case of pedal edema; all were considered mild and resolved spontaneously. Postprocedure surveys indicated that 95% of reporting physicians were “satisfied” or “highly satisfied” with device performance. Conclusions: Hysteroscopic morcellation of intrauterine pathology was accomplished safely with a high degree of physician satisfaction in 278 patients treated in diverse healthcare settings that are reflective of general community practice in the United States. (J GYNECOL SURG 32:318)

Molybdenum disulfide (MoS2), a representative hexagonal transition metal dichalcogenide (TMD), has been extensively exploited in biomedical applications due to its unique physicochemical properties and biocompatibility. However, the lack of adequate data regarding how MoS2 activates immunological responses of macrophages remains a key concern for its risk assessment. Here, we employ a combined theoretical and experimental approach to investigate the interactions of MoS2 and PEGylated MoS2 (MoS2-PEG) with macrophages. We first perform molecular dynamics simulations to examine the atomic-detailed interactions of MoS2 and MoS2-PEG nanoflakes with a realistic model of the macrophage membrane. We show that a small MoS2 nanoflake (edge length of 2.86 nm) is capable of penetrating the macrophage membrane independent of its concentration. We also demonstrate that when initiated with a corner point-on configuration, the surface-bound PEG chains of MoS2-PEG hinder its membrane insertion process, leading to a prolonged passage through the membrane. Moreover, when placed in a face-on arrangement initially, the MoS2-PEG exhibits a lower binding free energy than pristine MoS2 after its adsorption on the membrane surface. The PEG chains can even insert and get buried in the outer leaflet of the membrane, providing additional contact for membrane adsorption. Our flow cytometric experiments then show that the responses of macrophages to either MoS2-PEG or MoS2 are significantly higher than that of the control (no nanomaterial stimulus), with MoS2-PEG eliciting stronger cytokine secretion than the pristine MoS2. The characteristics of slower/prolonged membrane penetration and stronger membrane adsorption of MoS2-PEG compared to pristine MoS2 explain why it triggers more sustained stimulation and higher cytokine secretion in macrophages as observed in our experiments. Our findings reveal the underlying molecular mechanism of how MoS2-PEG influences the immune responses and suggest its potential applications in nanomedicine involving immune stimulation.

Abnormal peptide assembly and aggregation is associated with an array of neurodegenerative diseases including Alzheimer's disease (AD). A detailed understanding of how nanostructured materials such as oxidized graphene perturb the peptide assembly and subsequently induce fibril dissociation may open new directions for the development of potential AD treatments. Here, we investigate the impact of surface inhomogeneity of graphene oxide (GO) on the assembly of amyloid-beta Aβ

Membrane filtration processes for water desalination have been greatly improved thanks to rapid development of nanoporous 2-dimentional (2D) materials. Nanoporous graphene and molybdenum disulfide have proved to show promising properties for desalination. In this study, we detailly investigated the desalination performance of a different nanoporous 2D material, nanoporous boron nitride (BN), by Molecular Dynamics simulation. Our calculations demonstrated that nanoporous BN allows for rapid water permeability with effective salt rejection. The permeability is not only two orders of magnitude higher than existing commercial techniques but also much higher than nanoporous graphene and molybdenum disulfide membranes. We further showed that the pores with B-h edges or with N-h edges present different desalination efficiency. Compared to N-h pores, B-h pores have better desalination performance in term of higher water flux. To the best of our knowledge, nanoporous BN is the 2D material having the highest water permeability thus far while maintaining high salt rejection. Overall, our results shed light on the potential advantages of using nanoporous BN for water purification.

To assess fertility outcomes in infertile women after hysteroscopic morcellation of intrauterine lesions.Retrospective case series from 2 U.S. fertility clinics. Women with intrauterine pathology and infertility (≥6 months' duration if age ≥35, or ≥12 months' duration if age35) or recurrent pregnancy loss underwent hysteroscopic morcellation of intrauterine lesions. Main outcome mea- sures were postoperative pregnancies, live births, and procedure-related adverse events through 6 months.Of 101 women screened, 62 satisfied inclusion criteria and 44 (71%) conceived, resulting in 39 live births. Women who conceived were 37.1±4.6 years old (range, 28.0-46.8) at intervention; mean treatment-to-pregnancy interval was 8.4? 7.0 months (range, 1-32). Body mass index was lower in women who conceived (24.94.4 kg/M2 versus women who remained infertile (28.9±04 kg/IM2, p=0.0362). Of 67 lesions in women who conceived, fibroids, polyps, and adhesions comprised 21%, 70%, and 9%, respectively. Mean respective fibroid and polyp sizes in women who conceived were 2.1±1.3 and 1.4±0.8 cm, respectively, similar to those in women who did not conceive. Fibroids were 74% type 0 and 26% type 1. Lesion area eradication was 95.8±9.9% for fibroids and 100% for polyps. No serious/severe adverse events occurred.Morcellation of intrauterine pathologies in subfertile women undergoing fertility therapy safely supports postopera- tive pregnancy and live birth.

Unlike most matrix metalloproteinase (MMP) inhibitors, which target the conserved catalytic zinc site, Gd@C

BackgroundCurrent professional society guidelines recommend genetic carrier screening be offered on the basis of ethnicity, or when using expanded carrier screening panels, they recommend to compute residual risk based on ethnicity. We investigated the reliability of self-reported ethnicity in 9138 subjects referred to carrier screening. Self-reported ethnicity gathered from test requisition forms and during post-test genetic counseling, and genetic ancestry predicted by a statistical model, were compared for concordance.ResultsWe identified several discrepancies between the two sources of self-reported ethnicity and genetic ancestry. Only 30.3% of individuals who indicated Mediterranean ancestry during consultation self-reported this on requisition forms. Additionally, the proportion of individuals who reported Southeast Asian but were estimated to have a different genetic ancestry was found to depend on the source of self-report. Finally, individuals who reported Latin American demonstrated a high degree of ancestral admixture. As a result, carrier rates and residual risks provided for patient decision-making are impacted if using self-reported ethnicity.ConclusionOur analysis highlights the unreliability of ethnicity classification based on patient self-reports. We recommend the routine use of pan-ethnic carrier screening panels in reproductive medicine. Furthermore, the use of an ancestry model would allow better estimation of carrier rates and residual risks.

Experimental ooplasmic transplantation from donor to recipient oocyte took place between 1996 and 2001 at Saint Barnabas Medical Center, USA. Indication for 33 patients was repeated implantation failure. Thirteen couples had 17 babies. One patient delivered twins from mixed ooplasmic and donor egg embryos. A limited survey-based follow-up study on the children is reported: 12 out of 13 parents completed a questionnaire on pregnancy, birth, health, academic performance and disclosure. Parents of a quadruplet did not participate. Prenatal development and delivery were uneventful. School grades ranged from good to excellent. Children were of good health. Body mass index (BMI) was normal in 12 out of 13 children. One child had chronic migraine headaches, two mild asthma, three minor vision and three minor skin problems. One boy from a boy/girl twin was diagnosed with borderline pervasive developmental disorder - not otherwise specified at age 18 months, but with no later symptoms. One couple disclosed the use of egg donor to their child. One reported intention to disclose; six were undecided and four reported they would not disclose. This limited follow-up strategy presents a high risk of bias. Parents may not assent to standardized clinical analysis owing to lack of disclosure to their children.

Knowledge-based or Artificial Intelligence techniques are used increasingly as alternatives to more classical techniques to model environmental systems. We review some of them and their environmental applicability, with examples and a reference list. The techniques covered are case-based reasoning, rule-based systems, artificial neural networks, fuzzy models, genetic algorithms, cellular automata, multi-agent systems, swarm intelligence, reinforcement learning and hybrid systems.

Three species of ectomycorrhizal fungi (Hebeloma crustuliniforme, Suillus variegatus and Cenococcum geophilum) were grown in axenic culture amended with range of AsO43– concentration under three different PO43– regimes. The fungi exhibited different growth responses to AsO43– that varied with PO43– concentration. Suillus variegatus showed the greatest sensitivity to AsO43–, with growth almost completely inhibited in the presence of AsO43– under the lower two PO43– treatments. Under the highest PO43– treatment however, growth was enhanced and S. variegatus was able to persist at AsO43– concentrations of up to 4 mM. Hebeloma crustuliniforme also showed high sensitivity to AsO43– especially at low PO43– concentration. The two higher PO43– treatments had an ameliorating effect on AsO43– toxicity in H. crustuliniforme. This demonstrates the ability of PO43– to alleviate AsO43– toxicity. The response from S. variegatus and H. crustuliniforme, both basidiomycetes, was in contrast to the ascomycete C. geophilum. This fungus demonstrated tolerance to AsO43– when grown in culture solution and PO43– did not have an ameliorating effect on AsO43– toxicity in C. geophilum. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

To determine whether maternal balanced translocation is a risk factor for poor ovarian response to controlled ovarian hyperstimulation (COH).A retrospective analysis.Private IVF center.All couples presenting to a single center for preimplantation genetic diagnosis (PGD) for autosomal balanced translocation in either partner from 1995 through 2001.Cycle parameters and embryology outcomes were examined and compared between two groups: 61 cycles in 46 women with balanced translocations compared with 42 cycles in 32 women whose male partner had a balanced translocation.Response to ovarian stimulation.In couples undergoing IVF/PGD to avoid transmission of an unbalanced karyotype, a significantly higher proportion of women carrying balanced translocations (female carrier) responded very poorly (E2 on the day of hCG1,000 pg/mL) to ovarian stimulation compared to women whose partner had a balanced translocation (male carrier) (23.0% vs. 7.1%).In couples undergoing IVF/PGD for balanced translocation, the risk for poor response to ovarian stimulation may be increased when the female partner carries the balanced translocation compared to when the male partner carries the translocation. Given significant embryo attrition due to chromosomal imbalance, aggressive stimulation should be considered if the patient does not have risk factors for ovarian hyperstimulation syndrome (OHSS).

To determine whether insulin-like growth factor-I (IGF-I) plays a role in rabbit corpus luteum (CL) physiology the authors examined: IGF-I expression, the effect of IGF-I on progesterone (P) production in vitro, and the interaction of IGF-I with estradiol, the primary luteotropin in the rabbit. Northern blot analysis revealed that IGF-I mRNA is present in the rabbit CL throughout pseudopregnancy. An intact ovarian in vitro perfusion model and dispersed luteal cell culture were used to determine the effects of IGF-I on P production and interactions with estradiol. IGF-I significantly stimulated P production compared to control medium by the isolated, intact perfused rabbit ovary and by dispersed, cultured luteal cells. Estradiol alone did not stimulate P production in vitro. Estradiol did augment IGF-I-stimulated P production in the intact perfused ovary and in luteal cell culture. These findings support a role for IGF-I in rabbit CL P production.

Although psychological evaluations are an integral element of screening for third-party reproduction and the Personality Assessment Inventory (PAI) is commonly used for these evaluations, little is known about the psychometric properties or normative scores on the PAI among egg donors and carriers. We evaluated the PAI among 1,044 egg donors and gestational carriers from various fertility clinics across the United States. PAI scales were generally internally consistent in this population, although range restriction appeared to attenuate reliability on several scales. The PAI profiles of egg donors and carriers had elevated positive impression management and suppressed clinical scale scores relative to the community standardization sample, as would be expected given the contingencies of this assessment context. Scores were similar across egg donors and carriers and were similar whether the carrier or donor was known or not known to the prospective parents. Sample-specific norms are provided for the use of the PAI in this setting.

Objective To clarify the role of P in ovulation, fertilization, and early embryonic development using RU486, a potent P receptor blocker. Design Ovulatory efficiency, IVF, and early embryonic development were evaluated after RU486 administration in vivo and in vitro. Setting Research laboratory of a university hospital. Participants Mature male and female New Zealand white rabbits. Interventions Animals were treated with RU486 or vehicle for 3days before hCG-induced ovulation. Ovaries treated with hCG to induce ovulation were perfused for 6hours in vitro with RU486 or vehicle. In vitro fertilization was performed in the presence or absence of RU486. Main Outcome Measures The percentage of mature follicles ovulating (ovulatory efficiency) was determined after in vivo and in vitro treatment. Fertilization, morula, and blastocyst development were evaluated every 24hours for 120hours. Results RU486 significantly inhibited ovulation, fertilization, and early embryonic development. Conclusions Progesterone plays a significant role in ovulation, fertilization, and preimplantation embryonic development.

BACKGROUND: Expanded carrier screening (ECS) is routinely offered to patients seeking fertility treatment. ECS provides an abundance of information for patients, which may inform reproductive decisions. However this volume of information may be perceived as causing anxiety, particularly for individuals identified as carriers. OBJECTIVE: Our aim was to assess the effect of ECS results on patients identified as carriers compared to non-carriers. MATERIALS & METHODS: Patients who underwent ECS were sent a survey 3 weeks after results were reported. Post-test genetic counseling (GC) was offered to all patients. Consenting participants were asked to report 1) with whom they discussed their results and 2) how often they felt a number of emotions post-test. Responses were compared between carriers and noncarriers. RESULTS: 420 patients completed the survey and were eligible for analysis. 178 were identified as carriers (42%). Post-test GC was received by 158 (89%) of carriers. When asked to report with whom they discussed results, carriers were significantly more likely to have discussed results with family members (p 1⁄4 0.0003). Among both carriers and non-carriers, most participants reported not discussing their results with a primary care provider/other medical professional. When reporting on emotions felt post-test, carriers felt anxious, nervous, and a loss of control significantly more often than non-carriers (p1⁄45.689e-05; Fisher p1⁄4 0.0005). While the difference here was significant, the overall frequency of feeling said emotions was low; the large majority of both carriers and non-carriers felt this way rarely/never. CONCLUSIONS: It is expected that carriers may feel anxiety regarding their results. However, even among carriers, the majority reported feeling these emotions rarely/never. This may be due to post-test GC. The benefit of ECS pairedwith GC extended to participants’ families, as carriers reported discussing results with their family members. Participants reported not discussing their results with other medical professionals. The clinical impact of this is important; despite discussing their results with a genetics professional, carriers may feel anxiety regarding how their carrier status affects other areas of their health. These emotions could be mitigated by the sharing of results with other healthcare providers. Future studies around facilitation of such discussions and the impact of post-test genetic counseling will be important, as will implementation of pre-test counseling for patients undergoing screening. FINANCIAL SUPPORT: Kumar, Yarnall, and Lee are employees of Recombine.

Beat-to-beat variability (BTBV) of the fetal heart rate (FHR) is considered an indication of the neural integrity and is an important prognostic indicator of fetal well-being. We report the initial evaluation of a recently developed abdominal fetal ECG (AFECG) mode of FHR monitoring using Adaptive Digital Filtering (ADF) to accurately obtain BTBV noninvasively. Five women in labor at term were monitored with the direct fetal scalp electrode (FSE) and simultaneously with the AFECG using ADF. A computer analysis of 3298 seconds (55 minutes) of data provided a one-to-one comparison of the R-R intervals. One analysis of the direct FSE data with a second simultaneous analysis from the same electrode, to serve as control, was compared with the noninvasive AFECG data. The study group has a standard deviation of only 1.50 bpm compared to 0.79 bpm for the control group. The AFECG method agrees with the direct FSE method within 1 bpm for 92.6% of the reported R-R intervals and within 2 bpm for 98.9% of the reported intervals. This new noninvasive AFECG technique with ADF provides a continuous record of instantaneous FHR and BTBV that may be relied upon to provide an accurate continuous clinical record. The reliability of the technique has yet to be determined over a wide range of subjects.

Three species of ectomycorrhizal fungi (Hebeloma crustuliniforme, Suillus variegatus and Cenococcum geophilum) were grown in axenic culture amended with range of AsO4(3-) concentration under three different PO4(3-) regimes. The fungi exhibited different growth responses to AsO4(3-) that varied with PO4(3-) concentration. Suillus variegatus showed the greatest sensitivity to AsO4(3-), with growth almost completely inhibited in the presence of AsO4(3-) under the lower two PO4(3-) treatments. Under the highest PO4(3-) treatment however, growth was enhanced and S. variegatus was able to persist at AsO4(3-) concentrations of up to 4 mM. Hebeloma crustuliniforme also showed high sensitivity to AsO4(3-) especially at low PO4(3-) concentration. The two higher PO4(3-) treatments had an ameliorating effect on AsO4(3-) toxicity in H. crustuliniforme. This demonstrates the ability of PO4(3-) to alleviate AsO4(3-) toxicity. The response from S. variegatus and H. crustuliniforme, both basidiomycetes, was in contrast to the ascomycete C. geophilum. This fungus demonstrated tolerance to AsO4(3-) when grown in culture solution and PO4(3-) did not have an ameliorating effect on AsO4(3-) toxicity in C. geophilum.

Objective To review milestones in the care of the infertile couple over the past five decades. Data Resources All issues of Fertility and Sterility were reviewed beginning with the first issue published in 1950 through volume 61, number 1 (January 1994). Other significant articles from the literature were reviewed as identified by directed Medline searches. Results This historical review gives the reader a sense of the evolution of modern reproductive technology—how the past has shaped the present—through the development of modern surgical techniques, methods of ovulation induction, laparoscopy, ultrasound, endocrine assays, in vitro fertilization, cryopreservation of sperm and preembryos, and microscopic procedures on gametes and preembryos. Conclusions The remarkable capabilities of modern reproductive technologies are only possible because of the culmination of decades of innovative research.