Miracle-dz/UniFAR-FTUs huggingface dataset:
Imaging histamine H3 receptors with [18F]FMH3: Test–retest and occupancy studies in the non‐human primate

A positron emission tomography (PET) radioligand, [18F]FMH3, has been developed to interrogate histamine receptor subtype 3 (H3R), where dysfunction at this site is linked with obesity, sleep abnormality, and cognitive disorders. [18F]FMH3 was evaluated for imaging central H3R sites in non‐human primates through test–retest (TRT) and dose‐receptor occupancy studies with two selective H3R antagonists in order to support clinical investigations. Two adult female baboons underwent [18F]FMH3 PET brain scans in the HR+, at repeated baseline (n = 7) and following administration of escalating doses of ABT‐239 (0.003–0.1m/kg, n = 4) and ciproxifan (0.5–2.1 mg/kg, n = 7). Volume of distribution (VT) in brain regions was estimated using the 2‐tissue compartment model. TRT variability of VT across repeated baseline scans was reported as % coefficient of variation (COV). ABT‐239 and ciproxifan occupancy at H3R was estimated using the occupancy plot, and the relationship of occupancy with dose and plasma levels was determined. In baboons, distribution of [18F]FMH3 was high in the striatum, intermediate in cortical regions, and low in the brain stem. COV of baseline VT was 7.0 ± 3.5%, averaged across regions and animals. Dose‐dependent effects of ABT‐239 and ciproxifan measured the brain. ED50 and EC50, respectively, were 0.011 mg/kg and 0.942 ng/ml for ABT‐239 and 0.73 mg/kg and 208.3 ng/ml for ciproxifan. [18F]FMH3 demonstrated high TRT reliability and can be used to measure occupancy of H3R‐targeted drugs. Validation in non‐human primates support [18F]FMH3 PET studies toward clinical investigations of H3R.
Measurement of fusional vergence: a systematic review

ABSTRACT Background: Fusional amplitudes are important for clinical practice in diagnosing and managing binocular vision anomalies. Several measurement methods can be used to assess fusional amplitudes. However, those methods are not interchangeable, and measurement repeatability has been questioned. Objectives: To compare the normative values of tests for the measurement of fusional vergence and to investigate sources of heterogeneity of diagnostic accuracy including: age, variation in method of assessment, study design and size, type (convergent, divergent, vertical, cyclo) and severity of strabismus (constant/intermittent/latent). Data sources: Bibliographic databases were searched up to March 2018, including Cochrane registers, PubMed, Web of ScienceTM, Google Scholar and Science Citation Index. Trial registers and conference proceedings were hand searched. Review methods: The review observed and reported according to the PRISMA guidelines and was registered with PROSPERO. The I2 was used to show the percentage of observed total variation across studies that is due to real heterogeneity rather than chance. The results of the different studies and the overall effect (meta-analysis under the random effects model) are shown. Results: Eighty-one studies were included in the review. Heterogenous information about break vergence amplitudes is reported for the step vergence method (I2 > 50%; p < 0.05) in children. Four parameters were reported consistently to affect measurements; age, method of assessment, order of testing and target size. For the smooth vergence technique break vergence values heterogeneity was not present in children and adults (I2 = 0%; p > 0.05). Limitations: The results are based on cross-sectional studies that were performed independently of each other, with different examiners, methods of examination and different populations. Conclusions: The source of heterogeneity between studies for vergence break points measured with the step vergence method seems to be linked with age. Normal vergences reported in children had considerable heterogeneity compared with adults. In clinical practice, the population-based vergence ranges measured with the step vergence method in children should not be used as one single criterion. For the smooth vergence technique, normative population data can be used.
Measurement of emission lifetime dynamics and biexciton emission quantum yield of individual InAs colloidal nanocrystals.

The understanding of the photophysics of visible-emitting colloidal nanocrystals (NCs) has long been aided by single-molecule studies of their emission. Until recently, no suitable detection technologies have existed for corresponding studies of shortwave-infrared (SWIR) emitters. Now, the use of superconducting nanowire single-photon detectors (SNSPDs) enables the detailed study of SWIR NC emission dynamics at the single-emitter level. Here, we report a detailed analysis of the emission dynamics of individual InAs/CdZnS NCs emitting in the SWIR region. We observe blinking akin to the type A and type B blinking previously observed in visible-emitting CdSe NCs. We determine the intrinsic radiative lifetime of several InAs/CdZnS NCs and find examples ranging from 50–200 ns, indicative of a quasi-type-II electronic structure. We also measure g0(2) for several of these NCs and find that their biexciton emission quantum yields vary from <1% up to 43%.
Cell-free gene-regulatory network engineering with synthetic transcription factors

Significance Understanding basic mechanisms and engineering new systems in biology are hampered by the challenge of quantifying and manipulating numerous molecular components and their interactions. In this work, we present an approach to tackle these difficulties, by combining a cell-free system with a microfluidic platform for high-throughput measurements. We apply the system to comprehensively characterize a library of synthetic zinc-finger transcription factors, which are common building blocks of transcriptional regulatory networks. We subsequently use the knowledge gained to engineer highly specific, tunable, and strong cooperative repressors, which can be applied to carry out logical computation on promoters. Gene-regulatory networks are ubiquitous in nature and critical for bottom-up engineering of synthetic networks. Transcriptional repression is a fundamental function that can be tuned at the level of DNA, protein, and cooperative protein–protein interactions, necessitating high-throughput experimental approaches for in-depth characterization. Here, we used a cell-free system in combination with a high-throughput microfluidic device to comprehensively study the different tuning mechanisms of a synthetic zinc-finger repressor library, whose affinity and cooperativity can be rationally engineered. The device is integrated into a comprehensive workflow that includes determination of transcription-factor binding-energy landscapes and mechanistic modeling, enabling us to generate a library of well-characterized synthetic transcription factors and corresponding promoters, which we then used to build gene-regulatory networks de novo. The well-characterized synthetic parts and insights gained should be useful for rationally engineering gene-regulatory networks and for studying the biophysics of transcriptional regulation.
Proton MR spectroscopy in the breast: Technical innovations and clinical applications

Proton magnetic resonance spectroscopy (MRS) is a promising noninvasive diagnostic technique for investigation of breast cancer metabolism. Spectroscopic imaging data may be obtained following contrast‐enhanced MRI by applying the point‐resolved spectroscopy sequence (PRESS) or the stimulated echo acquisition mode (STEAM) sequence from the MR voxel encompassing the breast lesion. Total choline signal (tCho) measured in vivo using either a qualitative or quantitative approach has been used as a diagnostic test in the workup of malignant breast lesions. In addition to tCho metabolites, other relevant metabolites, including multiple lipids, can be detected and monitored. MRS has been heavily investigated as an adjunct to morphologic and dynamic MRI to improve diagnostic accuracy in breast cancer, obviating unnecessary benign biopsies. Besides its use in the staging of breast cancer, other promising applications have been recently investigated, including the assessment of treatment response and therapy monitoring. This review provides guidance on spectroscopic acquisition and quantification methods and highlights current and evolving clinical applications of proton MRS.
Functionalized photosensitive gelatin nanoparticles for drug delivery application

Abstract In this study, zinc phthalocyanine (ZnPc) was loaded onto gelatin nanoparticles functionalized with polyelectrolytes (polystyrene sulfonate/polyallylamine hydrochloride) by layer-by-layer (LbL) assembly. The process yield and the encapsulation efficiency were 76.0% ± 2.5 and 86.0% ± 1.8, respectively. The functionalized photosensitive gelatin nanoparticles (FPGN) had a mean diameter of 396.5 ± 45.8 nm, narrow distribution size with a polydispersity index of 0.106. The obvious switching of zeta potential indicates successful alternating deposition of the polyanion PSS and polycation PAH directly on the gelatin nanoparticles. The in vitro drug release investigation found that the LbL deposited polyelectrolyte bilayer is very efficient to reduce the release rate and assuage the initial burst for drugs loaded in gelatin nanoparticles. The photobiological activity of FPGN was evaluated on mouse macrophage carcinoma line J774 A-1. The cells viability decreased with the increase of the light dose in the range of 1–10.0 J.cm−2. ZnPc-loaded in functionalized gelatin nanoparticles are the release systems that promise photodynamic therapy use.
Screening for BK Viremia/Viruria and the Impact of Management of BK Virus Nephropathy in Renal Transplant Recipients.

OBJECTIVES The prevalence of BK-induced nephritis in renal transplant recipients is estimated to be 1% to 10%; the rate of graft loss within 1 year is 30% to 65%. We conducted this study to evaluate screening of BK virus in blood and/or urine among renal transplant recipients and to assess the effects of different therapeutic modalities in renal transplant recipients with BK nephropathy. MATERIALS AND METHODS Kidney transplant recipients were screened at the time of transplant and then at 1, 2, 3, 6, 9, 12, 18, and 24 months posttransplant. Fiftynine patients were diagnosed with BK virus viremia. Patients were divided into 2 groups according to treatment: group 1 (n = 29) received an active treatment and group 2 (n = 30) received minimized immunosuppression. RESULTS Most patients required graft biopsies to confirm diagnosis (86.2% in group 1 vs 50% in group 2; P = .03). Both groups were comparable regarding demographic data. Initial posttransplant graft function was significantly better in group 1 (P = .017); ultimately, there was no significant difference between both groups regarding graft survival (P= .51). Fifty percent of patients had biopsy-proven acute T-cell-mediated rejection before BK virus-associated nephropathy diagnosis (significantly higher in group 1). Serum creatinine levels were significantly better in group 2 at 3, 4, and 5 years after BK nephropathy (P = .001, .017, and .003, respectively). CONCLUSIONS The prevalence of BK nephropathy in our renal transplant recipients was 5.9% with a rate of graft loss ranging from 43% to 51%. Regular screening, less intensive immunosuppressive therapy, and early intervention by reduction of immunosuppressive medications are advisable to obtain early diagnosis and to have better outcomes of BK virus-associated nephropathy with antiviral agents.
Virological Response and Hepatocarcinogenesis in Lamivudine-Resistant Hepatitis B Virus Genotype C Patients Treated with Lamivudine plus Adefovir Dipivoxil

Aims: The long-term efficacy of adefovir dipivoxil in combination with lamivudine to chronic hepatitis B virus (HBV) infection is still unclear. Methods: Virological response and hepatocarcinogenesis during lamivudine + adefovir were investigated in 183 lamivudine-resistant Japanese patients with chronic genotype C-dominant HBV infection. As the predictors of virological response, an assessment of clinical parameters and a nucleotide (nt) sequence analysis of the negative regulatory element to core gene (nt 1611–2450) were performed at the start of adefovir. Results: The cumulative HBV-DNA non-detectable and ALT normalization rates were 93.6 and 97.6% at the end of 3 years, respectively. Multivariate analysis identified total bilirubin, AST, and nt substitutions (nt 1762, 1768, 1846, 1896, 2134, 2288, 2441) as determinants of early non-detectable HBV-DNA. The yearly incidence of hepatocellular carcinoma (HCC) during the first 3 years was 2.7%. At the diagnosis of HCC, ALT normalization, HBV-DNA non-detectable, and HBeAg-seronegative conversion rates were 75.0, 83.3, and 57.1%, respectively. Furthermore, the cumulative HBV-DNA non-detectable and ALT normalization rates were not significantly different according to the development of HCC or not. Conclusions: Lamivudine-resistant patients treated with lamivudine + adefovir could achieve the excellent virological response and biochemical response, but the low hepatitis activity was not enough to suppress hepatocarcinogenesis.
Potential role of macrophages in experimental keratomycosis.

PURPOSE To investigate the potential role of macrophages in keratomycosis. METHODS Macrophage elimination was achieved by repeated subconjunctival injection of liposomes containing dichloromethylene diphosphonate (Cl(2)MDP-LIP) in BALB/c mice with Fusarium solani and Candida albicans keratitis, respectively. Controls received liposomes containing phosphate-buffered saline (PBS-LIP). Infected corneas were homogenized for colony counts. Immunohistochemistry was used to determine the efficiency of macrophage depletion. The cytokine production of Th1 cells, expressed by IFN-gamma and IL-12, and of Th2 cells, expressed by IL-4 and IL-10, in corneas was analyzed by enzyme-linked immunosorbent assay. Cytokine mRNA levels were detected by real-time polymerase chain reaction. Toll-like receptor 4 (TLR4) expression and mRNA levels were also examined. Immunoblotting and immunofluorescence staining were performed to evaluate the correlation between macrophages and TLR4 distribution. RESULTS Histopathologically, more severe keratomycosis developed in the mice treated with Cl(2)MDP-LIP than those treated with PBS-LIP 5 and 7 days after inoculation. In the Cl(2)MDP-LIP-treated group, little expression of macrophages could be detected in the conjunctiva and cornea. Numerous colonies were observed. There was a marked decrease of Th1 and Th2 cytokine production and mRNA expression, and TLR4 was significantly upregulated. Immunofluorescence staining demonstrated that partial F4/80(+) cells were TLR4(+). There was a positive correlation between TLR4 mRNA and IFN-gamma mRNA expression. CONCLUSIONS Local depletion of macrophages may downregulate the immune response and aggravate fungal keratitis. Macrophages appear to play an important role in host defense against corneal infection of F. solani and C. albicans.
Patients with rheumatic diseases share similar patterns of healthcare resource utilization

Objectives: Healthcare service needs have changed with the use of effective treatment strategies. Using data from the modern era, we aimed to explore and compare health service-related direct costs in juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), rheumatoid arthritis (RA), and axial spondyloarthritis (AxSpA). Methods: We linked a longitudinal, population-based clinical data set from Finland’s largest non-university hospital’s rheumatology clinic with an administrative database on health service-related direct costs in 2014. We compared all-cause costs and costs of comorbidities between adult patients with JIA, PsA, RA, and AxSpA (including ankylosing spondylitis). We also characterized patients with high healthcare resource utilization. Results: Cost distributions were similar between rheumatic diseases (p = 0.88). In adulthood, patients with JIA displayed a similar economic burden to much older patients with other inflammatory rheumatic diseases. A minority were high utilizers: among 119 patients with JIA, 15% utilized as much as the remaining 85%. For PsA (213 patients), RA (1086), and AxSpA (277), the high-utilization proportion was 10%. Both low and high utilizers showed rather low disease activity, but in high utilizers, the patient-reported outcomes were slightly worse, with the most distinct differences in pain levels. Of health service-related direct costs, index rheumatic diseases comprised only one-third (43.6% in JIA) and the majority were comorbidity costs. Conclusions: Patients with JIA, PsA, RA, and AxSpA share similar patterns of healthcare resource utilization, with substantial comorbidity costs and a minority being high utilizers. Innovations in meeting these patients’ needs are warranted.
When pigs fly: emotional support animals, service dogs and the politics of legitimacy across species boundaries

This paper probes the distinction between the so-called emotional support animals (ESAs), a term that is specific to the USA and that has recently been the subject of significant media attention, and service animals. The attention devoted to ESAs has largely taken on the form of jokes and critical comments related to the absurdity of the ‘political correctness’ that makes it possible for pigs to fly in the passenger cabin of airplanes and llamas to accompany their owners on trips to the supermarket. Much criticism is meted out, also from within the disability community, against animal guardians who try to ‘pass their animals off’ as service dogs and ESAs, with a call for the establishment of clear-cut criteria for the definition of ESAs and service animals. The paper’s methodology is an analysis of the media accounts of legitimate and illegitimate service animals; an analysis that reveals how the boundary between legitimate and illegitimate is constructed through the building blocks of these stories. ESAs are something of a limit case that points to the cultural paradoxes that govern Americans’ relationships with companion animals and with concepts of disability. The paper also argues that the insistence on establishing firm boundaries between ‘legitimate’ service animals and ESAs actually fosters a politics of suspicion, which can easily slip into suspicion directed at the human handlers of the animals.
Neurourology and Urodynamics

Funding information Research on Women’s Health Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health and National Institute on Child and Human Development; National Institute on Child and Human Development Abstract Aims: Pubovisceral (PV) muscle tears are associated with pelvic floor disorders. The goal of this study was to determine whether index finger palpatory assessment of PV muscle body integrity through the lateral vaginal wall is a reliable indicator of PV muscle tear severity diagnosed by magnetic resonance imaging (MRI). Methods: We studied 85 women, 7 weeks after vaginal birth. All had at least one risk factor for obstetric‐related PV muscle tear. The ordinal outcome measure of MRI‐documented PV muscle tear was defined as: none, less than 50% unilateral tear, 50% or greater unilateral tear or less than 50% bilateral tear, and 50% or greater bilateral tear. PV muscle body integrity by palpatory assessment was scored on a matrix, with each side scored independently and classified as PV muscle body “present” (assuredly felt), “equivocal” (not sure if felt), or “absent” (assuredly not felt). Proportional odds models were constructed to estimate the relationship between PV muscle body integrity palpatory assessment and MRI‐documented PV muscle tears. Results: Thirty‐five percent of study participants exhibited varying degrees of MRI‐documented PV muscle tears. Using palpatory assessment, we identified “PV muscle body present bilaterally” in 20%, “equivocal unilaterally or present contralaterally” in 8%, “equivocal or absent unilaterally” or “equivocal bilaterally” in 62%, and “absent bilaterally” in 9%. The odds ratio for estimating MRI results from palpatory assessment was 3.62 (95% confidence interval = 1.70‐7.73, P= 0.001). Conclusions: A rapid and inexpensive palpatory assessment in the clinic was highly associated with the risk of MRI‐documented PV muscle tear and is a useful component of a clinical assessment.
Impact of dosing frequency (once daily or twice daily) on patient adherence to oral targeted therapies for hematologic malignancies: a retrospective cohort study among managed care enrollees

Purpose Existing studies evaluating patient adherence to oral targeted therapies such as tyrosine kinase inhibitors focus on small populations with single malignancies. This study evaluated patterns of use of oral agents in a larger population across multiple hematologic malignancies. Methods Adult patients diagnosed with a hematologic malignancy and prescribed oral targeted therapy between 2011 and 2016 (N = 18,976) were identified from the MarketScan Commercial Claims and Encounters, and Medicare Supplemental databases. Eligible patients were enrolled in monthly prescription plans 6 months before and 12 months after the index date (date of first prescription claim; n = 2442). Multivariable logistic regressions were used to determine predictors of adherence using the medication possession ratio (MPR) and persistence through prescription refill gaps. Results The overall median adherence was 0.9 (MPR ≥ 80%) and was comparable between once-daily (QD) and twice-daily (BID) groups. Overall, 59% of patients were persistent at 12 months. Patients on QD and BID products did not have any significant differences in adherence (fixed-interval MPR, odds ratio 0.94; 95% confidence interval (CI), 0.75–1.18) or persistence (odds ratio 0.93; 95% CI, 0.75–1.17) 12 months from index. Significant predictors of adherence and persistence included patient age, total inpatient admissions, number of adverse events, and total hospital visits. Conclusion Patient-specific clinical factors, rather than regimen-specific factors, were the main predictors of oral targeted therapy adherence and persistence. Adherence to oral targeted therapies appears to be similar for patients on QD and BID regimens in the real-world setting.
AVR2 Targets BSL Family Members, Which Act as Susceptibility Factors to Suppress Host Immunity

Late blight pathogen Phytophthora infestans uses effector Avr2 to target BSL phosphatases to suppress plant immunity. To be successful plant pathogens, microbes use “effector proteins” to manipulate host functions to their benefit. Identifying host targets of effector proteins and characterizing their role in the infection process allow us to better understand plant–pathogen interactions and the plant immune system. Yeast two-hybrid analysis and coimmunoprecipitation were used to demonstrate that the Phytophthora infestans effector AVIRULENCE 2 (PiAVR2) interacts with all three BRI1-SUPPRESSOR1-like (BSL) family members from potato (Solanum tuberosum). Transient expression of BSL1, BSL2, and BSL3 enhanced P. infestans leaf infection. BSL1 and BSL3 suppressed INFESTIN 1 elicitin-triggered cell death, showing that they negatively regulate immunity. Virus-induced gene silencing studies revealed that BSL2 and BSL3 are required for BSL1 stability and show that basal levels of immunity are increased in BSL-silenced plants. Immune suppression by BSL family members is dependent on the brassinosteroid-responsive host transcription factor CIB1/HBI1-like 1. The P. infestans effector PiAVR2 targets all three BSL family members in the crop plant S. tuberosum. These phosphatases, known for their role in growth-promoting brassinosteroid signaling, all support P. infestans virulence and thus can be regarded as susceptibility factors in late blight infection.