Pathogenic missense variation in PABPC1L/EPAB causes female infertility due to oocyte maturation arrest at the germinal vesicle stage.

Women undergoing controlled ovarian hyperstimulation prior to in vitro fertilization (IVF) are treated using various protocols to induce multiple follicular growths. Complete failure of all oocytes to mature during IVF cycles is rare; however, it is a known cause of primary female infertility. Recently, pathogenic variations in a few genes have been identified in women with oocyte maturation defects; however, the underlying genetic causes remain largely unknown.This study included a Turkish family comprising three sisters with recurring oocyte maturation arrest at the germinal vesicle stage after multiple ovarian stimulations. Exome sequencing revealed a homozygous missense variant (c.1037C>T, p.Ala346Val) in the EPAB gene (also known as PABPC1L) in all three affected sisters, which was either absent or heterozygous in the unaffected family members. Functional experiments confirming the pathogenicity of the variant were performed by transfecting HEK293T cells and demonstrated the instability and increased rate of proteolysis of the mutated PABPC1L/EPAB protein. The identified variant, located in the well-conserved fourth RNA recognition motif (RRM4), in silico 3D modelling suggested changes in the physical properties of the pathogenic variant of PABPC1L/EPAB. Our findings validate PABPC1L/EPAB as an essential genetic contributor to the oocyte maturation process in humans and have direct implications for the genetic counselling of patients and their family members.

Hearing impairment amongst people with Osteogenesis Imperfecta in Germany.

INTRODUCTION: Hearing impairment concerns a relevant percentage of individuals with Osteogenesis Imperfecta (OI). When looking at the current literature, the percentage of affected individuals with OI varies greatly from 32 to 58% of patients having mild OI and 21% to 27% of patients having moderate to severe OI. Little is known about the German population with OI. METHOD: The goal of this study was to detect how many patients with OI, who visited the annual meeting of the German Association for Osteogenesis Imperfecta in 2023, proved to have a hearing impairment. In this prospective, cross-sectional study, each included individual obtained ear microscopy, audiometry, stapedius reflexes, tympanometry, and OAEs. Furthermore, each patient was asked a set of questions concerning the medical history. RESULTS: Of the included patients, 33% had hearing impairment. A significant difference was found for the mean air-bone gap (ABG) as well as the hearing threshold of the right ears. The difference was found between OI type III and IV (p = 0.0127) for the mean ABG and OI type I and IV (p = 0.0138) as well as III and IV (p = 0.0281) for the hearing threshold. Spearman's rank correlation showed a high correlation between age and hearing threshold. Of the patients between 40 and 50 years old, 56% had hearing loss. CONCLUSION: Hearing loss in individuals with OI is still a relevant problem, especially age-related in OI type I. Audiometry should be performed at least when individuals experience subjective hearing loss. The implementation of a screening starting at 40 years should be discussed and studied.

Events as Elements of Physical Observation: Experimental Evidence.

It is argued that all physical knowledge ultimately stems from observation and that the simplest possible observation is that an event has happened at a certain space-time location X→=x→,t. Considering historic experiments, which have been groundbreaking in the evolution of our modern ideas of matter on the atomic, nuclear, and elementary particle scales, it is shown that such experiments produce as outputs streams of macroscopically observable events which accumulate in the course of time into spatio-temporal patterns of events whose forms allow decisions to be taken concerning conceivable alternatives of explanation. Working towards elucidating the physical and informational characteristics of those elementary observations, we show that these represent hugely amplified images of the initiating micro-events and that the resulting macro-images have a cognitive value of 1 bit and a physical value of Wobs=Eobsτobs≫h. In this latter equation, Eobs stands for the energy spent in turning the initiating micro-events into macroscopically observable events, τobs for the lifetimes during which the generated events remain macroscopically observable, and h for Planck's constant. The relative value Gobs=Wobs/h finally represents a measure of amplification that was gained in the observation process.

Elementary Observations: Building Blocks of Physical Information Gain.

In this paper, we are concerned with the process of experimental information gain. Building on previous work, we show that this is a discontinuous process in which the initiating quantum-mechanical matter-instrument interactions are being turned into macroscopically observable events (EOs). In the course of time, such EOs evolve into spatio-temporal patterns of EOs, which allow conceivable alternatives of physical explanation to be distinguished. Focusing on the specific case of photon detection, we show that during their lifetimes, EOs proceed through the four phases of initiation, detection, erasure and reset. Once generated, the observational value of EOs can be measured in units of the Planck quantum of physical action h=4.136×10-15eVs. Once terminated, each unit of entropy of size kB=8.617×10-5eV/K, which had been created in the instrument during the observational phase, needs to be removed from the instrument to ready it for a new round of photon detection. This withdrawal of entropy takes place at an energetic cost of at least two units of the Landauer minimum energy bound of ELa=ln⁡2kBTD for each unit of entropy of size kB.

Measurement of the α-Particle Monopole Transition Form Factor Challenges Theory: A Low-Energy Puzzle for Nuclear Forces?

We perform a systematic study of the α-particle excitation from its ground state 0_{1}^{+} to the 0_{2}^{+} resonance. The so-called monopole transition form factor is investigated via an electron scattering experiment in a broad Q^{2} range (from 0.5 to 5.0 fm^{-2}). The precision of the new data dramatically supersedes that of older sets of data, each covering only a portion of the Q^{2} range. The new data allow the determination of two coefficients in a low-momentum expansion, leading to a new puzzle. By confronting experiment to state-of-the-art theoretical calculations, we observe that modern nuclear forces, including those derived within chiral effective field theory that are well tested on a variety of observables, fail to reproduce the excitation of the α particle.

Optical analysis of glutamate spread in the neuropil.

Fast synaptic communication uses diffusible transmitters whose spread is limited by uptake mechanisms. However, on the submicron-scale, the distance between two synapses, the extent of glutamate spread has so far remained difficult to measure. Here, we show that quantal glutamate release from individual hippocampal synapses activates extracellular iGluSnFr molecules at a distance of >1.5 µm. 2P-glutamate uncaging near spines further showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-Rs and N-methyl-D-aspartate (NMDA)-Rs respond to distant uncaging spots at approximately 800 and 2000 nm, respectively, when releasing the amount of glutamate contained in approximately five synaptic vesicles. The uncaging-induced remote activation of AMPA-Rs was facilitated by blocking glutamate transporters but only modestly decreased by elevating the recording temperature. When mimicking release from neighboring synapses by three simultaneous uncaging spots in the microenvironment of a spine, AMPA-R-mediated responses increased supra-additively. Interfering with extracellular glutamate diffusion through a glutamate scavenger system weakly reduced field synaptic responses but not the quantal amplitude. Together, our data suggest that the neuropil is more permissive to short-range spread of transmitter than suggested by theory, that multivesicular release could regularly coactivate nearest neighbor synapses and that on this scale glutamate buffering by transporters primarily limits the spread of transmitter and allows for cooperative glutamate signaling in extracellular microdomains.

Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting.

BACKGROUND: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers. METHODS: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed. RESULTS: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID. CONCLUSION: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.

Evaluation of auditory pathway excitability using a pre-operative trans-tympanic electrically evoked auditory brainstem response under local anesthesia in cochlear implant candidates.

OBJECTIVE: Subjective promontory stimulation is used to evaluate cochlear implant (CI) candidacy, but the test reliability is low. Electrically evoked auditory brainstem response (EABR) can verify the function of the auditory system objectively. This study's procedure uses a trans-tympanic rounded bent-tip electrode to perform pre-operative EABR under local anaesthesia (LA-TT-EABR) using MED-EL Software and Hardware. This study aimed to determine usability and effectiveness for CI candidates. DESIGN: We hypothesised that LA-TT-EABR waveforms of good quality would be related to successful hearing outcomes. We assumed that the duration of hearing loss/deafness was a confounding factor to study outcomes. STUDY SAMPLE: 19 borderline CI candidates. RESULTS: Positive LA-TT-EABR results were confirmed in 14 patients. LA-TT-EABR's mean latency was 2.05 ± 0.31 ms (eII/eIII) and 4.24 ± 0.39 ms (eIV/eV). Latencies weren't statistically different from intra-operative EABR elicited by basal CI contacts. All positive LA-TT-EABR patients benefitted from CI and speech performance improved one year after implantation. One patient with negative LA-TT-EABR was cochlear-implanted and had no hearing sensation. CONCLUSIONS: LA-TT-EABR is a tool in the frame of pre-operative objective testing the auditory pathway. It seems useful for clinical testing CI candidacy. Based on this study's outcomes, LA-TT-EABR should be recommended for uncertain CI candidates.

Engineering of dense arrays of Vertical Si1-xGexnanostructures.

Vertical nanostructure technologies are becoming more important for the down scaling of nanoelectronic devices such as logic transistors or memories. Such devices require dense vertical nanostructured channel arrays (VNCA) that can be fabricated through a top-down approach based on group IV materials. We present progresses on the top-down fabrication of highly anisotropic and ultra-dense Si1-xGex(x= 0, 0.2, 0.5) VNCAs. Dense nanowire and nanosheet patterns were optimized through high resolution lithography and transferred onto Si1-xGexsubstrates by anisotropic reactive ion etching with a fluorine chemistry. The right gas mixtures for a given Ge content resulted in perfectly vertical and dense arrays. Finally we fabricated oxide shell/SiGe core heterostructures by dry- and wet-thermal oxidation and evaluated their applicability for nanostructure size engineering, as already established for silicon nanowires. The impact of the nanostructured shape (wire or sheet), size and Ge content on the oxide growth were investigated and analysed in detail through transmission electron microscopy.

α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [223Ra]RaCl2-treated prostate cancer patients.

PURPOSE: One therapy option for prostate cancer patients with bone metastases is the use of [223Ra]RaCl2. The α-emitter 223Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [223Ra]RaCl2. METHODS: Multiple blood samples from nine prostate cancer patients were collected before and after administration of [223Ra]RaCl2, up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs. RESULTS: The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h - 4 weeks after administration), the α-track frequency remained elevated. CONCLUSION: The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from ß-emitters based on damage geometry.

Measurement of the helicity asymmetry E for the reaction γ p → π 0 p : The CBELSA/TAPS Collaboration.

A measurement of the double-polarization observable E for the reaction γ p → π 0 p is reported. The data were taken with the CBELSA/TAPS experiment at the ELSA facility in Bonn using the Bonn frozen-spin butanol (C 4 H 9 OH) target, which provided longitudinally-polarized protons. Circularly-polarized photons were produced via bremsstrahlung of longitudinally-polarized electrons. The data cover the photon energy range from E γ = 600 to 2310 MeV and nearly the complete angular range. The results are compared to and have been included in recent partial wave analyses.

[Interrater reliability of the criteria-based assessment of criminal responsibility in paraphilic disorders]. / Interrater-Reliabilität der kriteriengeleiteten Beurteilung der Schuldfähigkeit bei paraphilen Störungen.

BACKGROUND: For the assessment of criminal responsibility in the context of sexual delinquency, the evaluation of the severity of a paraphilic disorder and the ability to be controlled are of particular importance. Established assessment criteria are insufficiently operationalized. AIM AND METHODS: The existing criteria were tested by experts of various professional groups with respect to the reliability. For this purpose, 14 experts assessed the criteria of 2 different sets of criteria based on 2 case vignettes (see electronic supplementary material). RESULTS AND CONCLUSION: The interrater reliability (IRR) with reference to the criteria of Briken and Müller was higher than the previously established criteria of Boetticher et al. The evaluation of the subjective importance of the criteria of both assessment scales showed that all criteria were rated as at least of average importance. It could thus be useful to initially include both sets of criteria for a greater transparency in the assessment process and to investigate this procedure in further studies.

Linking hunting weaponry to attack strategies in sailfish and striped marlin.

Linking morphological differences in foraging adaptations to prey choice and feeding strategies has provided major evolutionary insights across taxa. Here, we combine behavioural and morphological approaches to explore and compare the role of the rostrum (bill) and micro-teeth in the feeding behaviour of sailfish (Istiophorus platypterus) and striped marlin (Kajikia audax) when attacking schooling sardine prey. Behavioural results from high-speed videos showed that sailfish and striped marlin both regularly made rostrum contact with prey but displayed distinct strategies. Marlin used high-speed dashes, breaking schools apart, often contacting prey incidentally or tapping at isolated prey with their rostra; while sailfish used their rostra more frequently and tended to use a slower, less disruptive approach with more horizontal rostral slashes on cohesive prey schools. Capture success per attack was similar between species, but striped marlin had higher capture rates per minute. The rostra of both species are covered with micro-teeth, and micro-CT imaging showed that species did not differ in average micro-tooth length, but sailfish had a higher density of micro-teeth on the dorsal and ventral sides of their rostra and a higher amount of micro-teeth regrowth, suggesting a greater amount of rostrum use is associated with more investment in micro-teeth. Our analysis shows that the rostra of billfish are used in distinct ways and we discuss our results in the broader context of relationships between morphological and behavioural feeding adaptations across species.

Observation of the pη

Data on the beam asymmetry Σ in the photoproduction of η mesons off protons are reported for tagged photon energies from 1130 to 1790 MeV (mass range from W=1748 MeV to W=2045 MeV). The data cover the full solid angle that allows for a precise moment analysis. For the first time, a strong cusp effect in a polarization observable has been observed that is an effect of a branch-point singularity at the pη^{'} threshold [E_{γ}=1447 MeV (W=1896 MeV)]. The latest BnGa partial wave analysis includes the new beam asymmetry data and yields a strong indication for the N(1895)1/2^{-} nucleon resonance, demonstrating the importance of including all singularities for a correct determination of partial waves and resonance parameters.

Impact of Coronavirus Outbreak on NO2 Pollution Assessed Using TROPOMI and OMI Observations.

Spaceborne NO2 column observations from two high-resolution instruments, Tropospheric Monitoring Instrument (TROPOMI) on board Sentinel-5 Precursor and Ozone Monitoring Instrument (OMI) on Aura, reveal unprecedented NO2 decreases over China, South Korea, western Europe, and the United States as a result of public health measures enforced to contain the coronavirus disease outbreak (Covid-19) in January-April 2020. The average NO2 column drop over all Chinese cities amounts to -40% relative to the same period in 2019 and reaches up to a factor of ~2 at heavily hit cities, for example, Wuhan, Jinan, while the decreases in western Europe and the United States are also significant (-20% to -38%). In contrast with this, although Iran is also strongly affected by the disease, the observations do not show evidence of lower emissions, reflecting more limited health measures.

G protein-coupled receptor 40 expression in human melanoma - correlation with tumour thickness, AJCC stage and survival.

BACKGROUND: In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein-coupled receptor GPR40, was identified in melanoma cells. OBJECTIVES: The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker. METHODS AND RESULTS: A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti-GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease-free survival (0.040). CONCLUSION: The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient's survival.

Photon Detection as a Process of Information Gain.

Making use of the equivalence between information and entropy, we have shown in a recent paper that particles moving with a kinetic energy ε carry potential information i p o t ( ε , T ) = 1 ln ( 2 ) ε k B   T relative to a heat reservoir of temperature T . In this paper we build on this result and consider in more detail the process of information gain in photon detection. Considering photons of energy E p h and a photo-ionization detector operated at a temperature T D , we evaluate the signal-to-noise ratio S N ( E p h , T D ) for different detector designs and detector operation conditions and show that the information gain realized upon detection, i r e a l ( E p h , T D ) , always remains smaller than the potential information i p o t ( E p h , T D ) carried with the photons themselves, i.e.,: i r e a l ( E p h , T D ) = 1 ln ( 2 ) ln ( S N ( E p h , T D ) ) ≤ i p o t ( E p h , T D ) = 1 ln ( 2 ) E p h k B T D   . This result is shown to be generally valid for all kinds of technical photon detectors, which shows that i p o t ( E p h , T D ) can indeed be regarded as an intrinsic information content that is carried with the photons themselves. Overall, our results suggest that photon detectors perform as thermodynamic engines that incompletely convert potential information into realized information with an efficiency that is limited by the second law of thermodynamics and the Landauer energy bounds on information gain and information erasure.

Observable and Unobservable Mechanical Motion.

A thermodynamic approach to mechanical motion is presented, and it is shown that dissipation of energy is the key process through which mechanical motion becomes observable. By studying charged particles moving in conservative central force fields, it is shown that the process of radiation emission can be treated as a frictional process that withdraws mechanical energy from the moving particles and that dissipates the radiation energy in the environment. When the dissipation occurs inside natural (eye) or technical photon detectors, detection events are produced which form observational images of the underlying mechanical motion. As the individual events, in which radiation is emitted and detected, represent pieces of physical action that add onto the physical action associated with the mechanical motion itself, observation appears as a physical overhead that is burdened onto the mechanical motion. We show that such overheads are minimized by particles following Hamilton's equations of motion. In this way, trajectories with minimum curvature are selected and dissipative processes connected with their observation are minimized. The minimum action principles which lie at the heart of Hamilton's equations of motion thereby appear as principles of minimum energy dissipation and/or minimum information gain. Whereas these principles dominate the motion of single macroscopic particles, these principles become challenged in microscopic and intensely interacting multi-particle systems such as molecules moving inside macroscopic volumes of gas.

It's never too late - balance and endurance training improves functional performance, quality of life, and alleviates neuropathic symptoms in cancer survivors suffering from chemotherapy-induced peripheral neuropathy: results of a randomized controlled trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) can affect functional performance and quality of life considerably. Since balance training has proven to enhance physical function, it might be a promising strategy to manage CIPN-induced functional impairments. METHODS: Fifty cancer survivors with persisting CIPN after finishing their treatment were randomly allocated to an intervention (IG) or active control group (CG). The IG did endurance plus balance training, the CG only endurance training (twice weekly over 12 weeks). Pre- and post-assessments included functional performance, cardiorespiratory fitness, vibration sense, and self-reported CIPN symptoms (EORTC QLQ-CIPN20). RESULTS: Intention-to-treat analyses (n = 41) did not reveal a significant group difference (CG minus IG) for sway path in semi-tandem stance after intervention (primary endpoint), adjusted for baseline. However, our per-protocol analysis of 37 patients with training compliance ≥70% revealed: the IG reduced their sway path during semi-tandem stance (- 76 mm, 95% CI -141 - -17; CG: -6 mm, 95% CI -52 - 50), improved the duration standing on one leg on instable surface (11 s, 95% CI 8-17; CG: 0 s, 95%CI 0-5) and reported decreased motor symptoms (-8points, 95% CI -18 - 0; CG: -2points 95% CI -6 - 2). Both groups reported reduced overall- (IG: -10points, 95% CI -17 - -4; CG: -6points, 95% CI -11 - -1) and sensory symptoms (IG: -7points, 95% CI -15 - 0; CG: -7points, 95% CI -15 - 0), while only the CG exhibited objectively better vibration sense (knuckle: 0.8points, 95% CI 0.3-1.3; IG: 0.0points, 95% CI -1.1 - 0.9; patella: 1.0points, 95% CI 0.4-1.6: IG: -0.8points, 95% CI -0.2 - 0.0). Furthermore, maximum power output during cardiopulmonary exercise test increased in both groups (IG and CG: 0.1 W/kg, 95% CI 0.0-0.2), but only the CG improved their jump height (2 cm, 95% CI 0.5-3.5; IG: 1 cm, 95% CI -0.4 - 3.2). CONCLUSION: We suppose that endurance training induced a reduction in sensory symptoms in both groups, while balance training additionally improved patients' functional status. This additional functional effect might reflect the IG's superiority in the CIPN20 motor score. Both exercises provide a clear and relevant benefit for patients with CIPN. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) number: DRKS00005419 , prospectively registered on November 19, 2013.

Effects of induced weight shift in the hind limbs on claw loads in dairy cows.

The modern dairy industry is plagued by a high prevalence of claw horn lesions in cows, which cause lameness, affect well-being, limit milk production, and are responsible for premature removal of cows from the herd. The lateral hind claws are primarily affected, and this has been linked to a relatively higher load being exerted on the lateral claws when cows shift weight from one hind limb to the other. The vertical ground reaction forces and mean and maximum pressures under the claws were measured in 40 nonlame dairy cows before and during a shift in weight from one hind limb to the other, which was accomplished by applying pressure manually to one side of the pelvis. During square standing on firm ground, about two-thirds of the entire hind limb load was exerted on the 2 lateral claws, and the remaining one-third was exerted on the medial claws combined. At the moment of maximum weight shift, the lateral claw of the loaded limb bore almost two-thirds of the entire load of both hind limbs, with the heel zone bearing almost half of the load of both hind limbs. Subsequently, the load of the lateral claw of the contralateral hind limb decreased, as did the load of both medial claws. Thus, the weight redistribution had occurred predominantly between the lateral hind claws. The high load exerted on a lateral hind claw during weight shift and at maximum weight shift is assumed to play a role in the pathogenesis of claw horn lesions, particularly when accentuated by a softened claw horn and hard flooring.