Quantifying Target Occupancy of Small Molecules Within Living Cells.

The binding affinity and kinetics of target engagement are fundamental to establishing structure-activity relationships (SARs) for prospective therapeutic agents. Enhancing these binding parameters for operative targets, while minimizing binding to off-target sites, can translate to improved drug efficacy and a widened therapeutic window. Compound activity is typically assessed through modulation of an observed phenotype in cultured cells. Quantifying the corresponding binding properties under common cellular conditions can provide more meaningful interpretation of the cellular SAR analysis. Consequently, methods for assessing drug binding in living cells have advanced and are now integral to medicinal chemistry workflows. In this review, we survey key technological advancements that support quantitative assessments of target occupancy in cultured cells, emphasizing generalizable methodologies able to deliver analytical precision that heretofore required reductionist biochemical approaches.

[Teaching otorhinolaryngology in times of COVID-19: to what extent can digital formats replace face-to-face teaching?] / Unterricht in der Hals-Nasen-Ohren-Heilkunde in Zeiten der COVID-19-Pandemie. Wie gut können digitale Formate die Präsenzlehre ersetzen?

OBJECTIVE: Due to the coronavirus disease 19 (COVID-19) pandemic, postgraduate training in otorhinolaryngology in 2020 was transferred completely from face-to-face to digital teaching. This paper assesses whether this change was possible without a reduction in the quality of teaching and learning. METHODS: Results of final written examinations were compared for the years 2016-2020, and the results of the teaching evaluation by the students for 2017-2020. The evaluation by students in 2020 included additional questions related to the switch from face-to-face to digital teaching. Additionally, the lecturers and teachers were asked for their assessments. RESULTS: Results of the final written examination did not show any significant differences between 2016-2019 and 2020. Students were highly satisfied with the digital format, but values did not reach the level of former years with face-to-face-teaching. Especially the interaction with patients and the teaching of manual skills were rated lower in the digital format. Lecturers emphasized the additional workload for preparation of digital teaching. CONCLUSION: The results of written examinations showed no difference between digital and face-to-face teaching. Online communication and interaction were reduced and regarded as cumbersome by students and faculty. Digital solutions providing more interaction and active participation are required. The digital format is more appropriate for teaching basic knowledge than for teaching practical skills.

Point Absorber Limits to Future Gravitational-Wave Detectors.

High-quality optical resonant cavities require low optical loss, typically on the scale of parts per million. However, unintended micron-scale contaminants on the resonator mirrors that absorb the light circulating in the cavity can deform the surface thermoelastically and thus increase losses by scattering light out of the resonant mode. The point absorber effect is a limiting factor in some high-power cavity experiments, for example, the Advanced LIGO gravitational-wave detector. In this Letter, we present a general approach to the point absorber effect from first principles and simulate its contribution to the increased scattering. The achievable circulating power in current and future gravitational-wave detectors is calculated statistically given different point absorber configurations. Our formulation is further confirmed experimentally in comparison with the scattered power in the arm cavity of Advanced LIGO measured by in situ photodiodes. The understanding presented here provides an important tool in the global effort to design future gravitational-wave detectors that support high optical power and thus reduce quantum noise.

Multitarget Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population.

INTRODUCTION: We set out to evaluate the performance of a multitarget stool DNA (MT-sDNA) in an average-risk colonoscopy-controlled colorectal cancer (CRC) screening population. MT-sDNA stool test results were evaluated against fecal immunochemical test (FIT) results for the detection of different lesions, including molecularly defined high-risk adenomas and several other tumor characteristics. METHODS: Whole stool samples (n = 1,047) were prospectively collected and subjected to an MT-sDNA test, which tests for KRAS mutations, NDRG4 and BMP3 promoter methylation, and hemoglobin. Results for detecting CRC (n = 7), advanced precancerous lesions (advanced adenoma [AA] and advanced serrated polyps; n = 119), and non-AAs (n = 191) were compared with those of FIT alone (thresholds of 50, 75, and 100 hemoglobin/mL). AAs with high risk of progression were defined by the presence of specific DNA copy number events as measured by low-pass whole genome sequencing. RESULTS: The MT-sDNA test was more sensitive than FIT alone in detecting advanced precancerous lesions (46% (55/119) vs 27% (32/119), respectively, P < 0.001). Specificities among individuals with nonadvanced or negative findings (controls) were 89% (791/888) and 93% (828/888) for MT-sDNA and FIT testing, respectively. A positive MT-sDNA test was associated with multiple lesions (P = 0.005), larger lesions (P = 0.03), and lesions with tubulovillous architecture (P = 0.04). The sensitivity of the MT-sDNA test or FIT in detecting individuals with high-risk AAs (n = 19) from individuals with low-risk AAs (n = 52) was not significantly different. DISCUSSION: In an average-risk screening population, the MT-sDNA test has an increased sensitivity for detecting advanced precancerous lesions compared with FIT alone. AAs with a high risk of progression were not detected with significantly higher sensitivity by MT-sDNA or FIT.

Tracking Dark Excitons with Exciton Polaritons in Semiconductor Microcavities.

Dark excitons are of fundamental importance for a wide variety of processes in semiconductors but are difficult to investigate using optical techniques due to their weak interaction with light fields. We reveal and characterize dark excitons nonresonantly injected into a semiconductor microcavity structure containing InGaAs/GaAs quantum wells by a gated train of eight 100 fs pulses separated by 13 ns by monitoring their interactions with the bright lower polariton mode. We find a surprisingly long dark exciton lifetime of more than 20 ns, which is longer than the time delay between two consecutive pulses. This creates a memory effect that we clearly observe through the variation of the time-resolved transmission signal. We propose a rate equation model that provides a quantitative agreement with the experimental data.

Quantum-Enhanced Advanced LIGO Detectors in the Era of Gravitational-Wave Astronomy.

The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Quality of life among women in Bangladesh following ileal conduit urinary diversion operations for irreparable vesicovaginal fistula and bladder exstrophy: observational study.

OBJECTIVE: To determine the quality of life (QOL) of fistula patients in Bangladesh who have undergone ileal conduit (IC) urinary diversion operations, and to assess whether the risks and ethical challenges involved, outweigh the reality of leaving a woman with urinary incontinence for the rest of her life. DESIGN: Observational study. SETTING: LAMB Hospital, Bangladesh. POPULATION: Seventeen women who had undergone IC between February 2012 and March 2016: 14 women previously had irreparable obstetric fistulas and three had bladder exstrophy. METHODS: Demographic, obstetric, IC-related, stigma and discrimination information were collected by questionnaire. Univariate analysis was done using the two-sided t-test for comparison of differences before and after IC surgery. MAIN OUTCOME METHODS: Change in stigma and discrimination scores. Health-related QOL assessed using the 36-item Short Form Health Survey. RESULTS: Of the 17 women, 14 (82.3%) felt they were cured of their fistula disease. Three complained of occasional leakage due to insufficient seal of the bag, mainly at night, and all but one experienced no limits to their daily activities. Stigma and discrimination scores were significantly lower after having the IC surgery. The mean difference from when the woman had a fistula to when she had an IC for stigma score was 3.17 (1.12-4.16, P < 0.001), and for discrimination score was 3 (1.9-4.1, P < 0.001). CONCLUSION: Overall, there has been improved QOL following IC among the women in this study and all would recommend IC to women in the same situation. They remain chronic patients with some physical symptoms, but are well re-integrated back into their communities. TWEETABLE ABSTRACT: Improved QOL following ileal conduit in women with persistent fistula related disorder in Bangladesh.

Health care provider communication training in rural Tanzania empowers HIV-infected patients on antiretroviral therapy to discuss adherence problems.

OBJECTIVES: Self-reported adherence assessment in HIV-infected patients on antiretroviral therapy (ART) is challenging and may overestimate adherence. The aim of this study was to improve the ability of health care providers to elicit patients' reports of nonadherence using a "patient-centred" approach in a rural sub-Saharan African setting. METHODS: A prospective interventional cohort study of HIV-infected patients on ART for ≥ 6 months attending an HIV clinic in rural Tanzania was carried out. The intervention consisted of a 2-day workshop for health care providers on patient-centred communication and the provision of an adherence assessment checklist for use in the consultations. Patients' self-reports of nonadherence (≥ 1 missed ART dose/4 weeks), subtherapeutic plasma ART concentrations (< 2.5th percentile of published population-based pharmacokinetic models), and virological and immunological failure according to the World Health Organization definition were assessed before and after (1-3 and 6-9 months after) the intervention. RESULTS: Before the intervention, only 3.3% of 299 patients included in the study reported nonadherence. Subtherapeutic plasma ART drug concentrations and virological and immunological failure were recorded in 6.5%, 7.7% and 14.5% of the patients, respectively. Two months after the intervention, health care providers detected significantly more patients reporting nonadherence compared with baseline (10.7 vs. 3.3%, respectively; P < 0.001), decreasing to 5.7% after 6-9 months. A time trend towards higher drug concentrations was observed for efavirenz but not for other drugs. The virological failure rate remained unchanged whereas the immunological failure rate decreased from 14.4 to 8.7% at the last visit (P = 0.002). CONCLUSIONS: Patient-centred communication can successfully be implemented with a simple intervention in rural Africa. It increases the likelihood of HIV-infected patients reporting problems with adherence to ART; however, sustainability remains a challenge.

Publisher's Note: Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen [Phys. Rev. Lett. 117, 082503 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.082503.

Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen.

We present an improved search for neutrinoless double-beta (0νßß) decay of ^{136}Xe in the KamLAND-Zen experiment. Owing to purification of the xenon-loaded liquid scintillator, we achieved a significant reduction of the ^{110m}Ag contaminant identified in previous searches. Combining the results from the first and second phase, we obtain a lower limit for the 0νßß decay half-life of T_{1/2}^{0ν}>1.07×10^{26} yr at 90% C.L., an almost sixfold improvement over previous limits. Using commonly adopted nuclear matrix element calculations, the corresponding upper limits on the effective Majorana neutrino mass are in the range 61-165 meV. For the most optimistic nuclear matrix elements, this limit reaches the bottom of the quasidegenerate neutrino mass region.

Size and albedo of Kuiper belt object 55636 from a stellar occultation.

The Kuiper belt is a collection of small bodies (Kuiper belt objects, KBOs) that lie beyond the orbit of Neptune and which are believed to have formed contemporaneously with the planets. Their small size and great distance make them difficult to study. KBO 55636 (2002 TX(300)) is a member of the water-ice-rich Haumea KBO collisional family. The Haumea family are among the most highly reflective objects in the Solar System. Dynamical calculations indicate that the collision that created KBO 55636 occurred at least 1 Gyr ago. Here we report observations of a multi-chord stellar occultation by KBO 55636, which occurred on 9 October 2009 ut. We find that it has a mean radius of 143 +/- 5 km (assuming a circular solution). Allowing for possible elliptical shapes, we find a geometric albedo of in the V photometric band, which establishes that KBO 55636 is smaller than previously thought and that, like its parent body, it is highly reflective. The dynamical age implies either that KBO 55636 has an active resurfacing mechanism, or that fresh water-ice in the outer Solar System can persist for gigayear timescales.

Utilization of a high-throughput shoot imaging system to examine the dynamic phenotypic responses of a C4 cereal crop plant to nitrogen and water deficiency over time.

The use of high-throughput phenotyping systems and non-destructive imaging is widely regarded as a key technology allowing scientists and breeders to develop crops with the ability to perform well under diverse environmental conditions. However, many of these phenotyping studies have been optimized using the model plant Arabidopsis thaliana. In this study, The Plant Accelerator(®) at The University of Adelaide, Australia, was used to investigate the growth and phenotypic response of the important cereal crop, Sorghum bicolor L. Moench and related hybrids to water-limited conditions and different levels of fertilizer. Imaging in different spectral ranges was used to monitor plant composition, chlorophyll, and moisture content. Phenotypic image analysis accurately measured plant biomass. The data set obtained enabled the responses of the different sorghum varieties to the experimental treatments to be differentiated and modelled. Plant architectural instead of architecture elements were determined using imaging and found to correlate with an improved tolerance to stress, for example diurnal leaf curling and leaf area index. Analysis of colour images revealed that leaf 'greenness' correlated with foliar nitrogen and chlorophyll, while near infrared reflectance (NIR) analysis was a good predictor of water content and leaf thickness, and correlated with plant moisture content. It is shown that imaging sorghum using a high-throughput system can accurately identify and differentiate between growth and specific phenotypic traits. R scripts for robust, parsimonious models are provided to allow other users of phenomic imaging systems to extract useful data readily, and thus relieve a bottleneck in phenotypic screening of multiple genotypes of key crop plants.

[Foetal Mortality in Singleton Foetuses at and beyond Term - An Analysis of German Perinatal Data 2004-2013]. / Fetale Mortalität bei Einlingen ab Termin - eine Analyse bundesdeutscher Perinataldaten 2004-2013.

BACKGROUND: Foetal mortality appears to increase in postmature pregnancies. There is debate on the optimal timing of induction of labour vs. watchful waiting. The literature on retrospective analyses of secondary data is inconclusive. Different approaches to calculate foetal risk exist. Recent and relevant data are needed in order to realise an appropriate discussion. MATERIAL AND METHODS: Mortality in singleton foetuses in Germany, between 2004 and 2013 was analysed in relation to gestational age. Risk for foetal death is described comparing stillbirths per 1,000 births at a particular gestational age (GA) vs. stillbirths per 1,000 ongoing pregnancies ("fetus-at-risk" model). Access to German routine perinatal data was granted. We included all stillbirths in singleton foetuses with no malformations after 36+6 weeks gestational age from 2004 until 2013. RESULTS: 5,933,117 births fulfilled our inclusion criteria. Foetal mortality per 1,000 births during that week of pregnancy is lowest between 41+0 and 41+6 days of (0.7/1,000). Mortality then increases to 2.3/1,000 in 42+0 to 42+6 GA. With the "fetus-at-risk" model, mortality is low between 37+0 and 39+6 GA, ranging from 0.2/1,000 ongoing pregnancies, increasing to 0.6/1,000 between 41+0 and 41+6, and 2.3/1,000 in the following week. For pregnancies lasting longer than 42+6 weeks, the stillbirth risk is identical at 6.3/1,000 with both calculation methods. CONCLUSION: Fetal mortality is low until 41+6 weeks of pregnancy. Interpretation of current data does not support a policy of routine IOL before this gestational age in singleton foetuses.

Patients who die during palliative radiotherapy. Status survey.

BACKGROUND AND PURPOSE: Palliative radiotherapy (RT) is routinely used in end of life care of patients with advanced malignancies; however, unnecessarily burdensome treatment shortly before death should be avoided. There is little knowledge on incidence and causes of intercurrent deaths during palliative RT. PATIENTS AND METHODS: In this study death events among inpatients receiving palliative RT between January 2009 and December 2011 at this department were retrospectively analyzed. Among epidemiological factors, treatment schedule and chronology, latency and duration of treatment in relation to the actual survival were identified. RESULTS: In this study 52 patients died during or shortly after palliative RT. Symptomatic bone metastases and brain metastases represented the most common RT indications. The general health status was poor with a median Karnofsky performance score of 50 %, RT was realized with a median single dose of 2.5 Gy to a median total dose of 30.5 Gy and was stopped prematurely in 73 % of patients. On average 53 % of the remaining lifetime was occupied by latency to starting RT. Once RT was begun the treatment duration required a median 64 % of the still remaining lifetime. CONCLUSION: The majority of patients who died had explicitly adverse pre-existing factors and rarely completed RT as scheduled. Latency to RT and RT duration occupied more than half of the remaining lifetime.

Observation of electron neutrino appearance in a muon neutrino beam.

The T2K experiment has observed electron neutrino appearance in a muon neutrino beam produced 295 km from the Super-Kamiokande detector with a peak energy of 0.6 GeV. A total of 28 electron neutrino events were detected with an energy distribution consistent with an appearance signal, corresponding to a significance of 7.3σ when compared to 4.92±0.55 expected background events. In the Pontecorvo-Maki-Nakagawa-Sakata mixing model, the electron neutrino appearance signal depends on several parameters including three mixing angles θ12, θ23, θ13, a mass difference Δm(32)(2) and a CP violating phase δ(CP). In this neutrino oscillation scenario, assuming |Δm(32)(2)|=2.4×10(-3) eV(2), sin(2)θ(23)=0.5, and Δm322>0 (Δm(32)(2)<0), a best-fit value of sin(2)2θ(13)=0.140(-0.032)(+0.038) (0.170(-0.037)(+0.045)) is obtained at δ(CP)=0. When combining the result with the current best knowledge of oscillation parameters including the world average value of θ(13) from reactor experiments, some values of δ(CP) are disfavored at the 90% C.L.

Precise measurement of the neutrino mixing parameter θ23 from muon neutrino disappearance in an off-axis beam.

New data from the T2K neutrino oscillation experiment produce the most precise measurement of the neutrino mixing parameter θ23. Using an off-axis neutrino beam with a peak energy of 0.6 GeV and a data set corresponding to 6.57×10(20) protons on target, T2K has fit the energy-dependent νµ oscillation probability to determine oscillation parameters. The 68% confidence limit on sin(2)(θ23) is 0.514(-0.056)(+0.055) (0.511±0.055), assuming normal (inverted) mass hierarchy. The best-fit mass-squared splitting for normal hierarchy is Δm32(2)=(2.51±0.10)×10(-3) eV(2)/c(4) (inverted hierarchy: Δm13(2)=(2.48±0.10)×10(-3) eV(2)/c(4)). Adding a model of multinucleon interactions that affect neutrino energy reconstruction is found to produce only small biases in neutrino oscillation parameter extraction at current levels of statistical uncertainty.

Measurement of the inclusive electron neutrino charged current cross section on carbon with the T2K near detector.

The T2K off-axis near detector ND280 is used to make the first differential cross-section measurements of electron neutrino charged current interactions at energies ∼1 GeV as a function of electron momentum, electron scattering angle, and four-momentum transfer of the interaction. The total flux-averaged ν(e) charged current cross section on carbon is measured to be ⟨σ⟩(ϕ)=1.11±0.10(stat)±0.18(syst)×10⁻³8 cm²/nucleon. The differential and total cross-section measurements agree with the predictions of two leading neutrino interaction generators, NEUT and GENIE. The NEUT prediction is 1.23×10⁻³8 cm²/nucleon and the GENIE prediction is 1.08×10⁻³8 cm²/nucleon. The total ν(e) charged current cross-section result is also in agreement with data from the Gargamelle experiment.