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Ice XIX and ice XV are both partly hydrogen-ordered counterparts to disordered ice VI. The ice XIX → XV transition represents the only order-to-order transition in ice physics. Using Raman and dielectric spectroscopies, we investigate the ambient-pressure kinetics of the two individual steps in this transition in real time (of hours), that is, ice XIX → transient ice VI (the latter called VI‡) and ice VI‡ → ice XV. Hydrogen-disordered ice VI‡ appears intermittent between 101 and 120 K, as inferred from the appearance and subsequent disappearance of the ice VI Raman marker bands. A comparison of the rate constants for the H2O ices reported here with those from D2O samples [Thoeny et al., J. Chem. Phys. 156, 154507 (2022)] reveals a large kinetic isotope effect for the ice XIX decay, but a much smaller one for the ice XV buildup. An enhancement of the classical overbarrier rate through quantum tunneling for the former can provide a possible explanation for this finding. The activation barriers for both transitions are in the 18–24 kJ/mol range, which corresponds to the energy required to break a single hydrogen bond. These barriers do not show an H/D isotope effect and are the same, no matter whether they are derived from Raman scattering or from dielectric spectroscopy. These findings favor the notion that a dipolar reorientation, involving the breakage of a hydrogen bond, is the rate determining step at the order-to-order transition. [ABSTRACT FROM AUTHOR]

Chemical evolution models predict a gradual build-up of 13C in the Universe, based on empirical nuclear reaction rates and assumptions on the properties of stellar populations. However, old metal-poor stars within the Galaxy contain more 13C than is predicted, suggesting that further refinements to the models are necessary. Gas at high-redshift provides important supplementary information at metallicities |$-2\lesssim \left[{\rm Fe/H}\right]\lesssim -1$|⁠ , for which there are only a few measurements in the Galaxy. We obtained new, high-quality, VLT/ESPRESSO observations of the QSO B1331 |$+$| 170 and used them to measure 12C/13C in the damped Lyman- |$\alpha$| system (DLA) at |$z_{\rm abs}=1.776$|⁠ , with |$\left[{\rm Fe/H}\right]$| = −1.27. ai-vpfit , an artificial intelligence tool based on genetic algorithms and guided by a spectroscopic information criterion, was used to explore different possible kinematic structures of the carbon gas. Three hundred independent ai-vpfit models of the absorption system were produced using pre-set 12C/13C values, ranging from 4 to 500. Our results show that |${\rm ^{12}C / ^{13}C}=28.5^{+51.5}_{-10.4}$|⁠ , suggesting a possibility of 13C production at low metallicity. [ABSTRACT FROM AUTHOR]

Astronomical precision spectroscopy underpins searches for life beyond Earth, direct observation of the expanding Universe and constraining the potential variability of physical constants on cosmological scales. Laser frequency combs can provide the required accurate and precise calibration to the astronomical spectrographs. For cosmological studies, extending the calibration with such astrocombs to the ultraviolet spectral range is desirable, however, strong material dispersion and large spectral separation from the established infrared laser oscillators have made this challenging. Here, we demonstrate astronomical spectrograph calibration with an astrocomb in the ultraviolet spectral range below 400 nm. This is accomplished via chip-integrated highly nonlinear photonics in periodically-poled, nano-fabricated lithium niobate waveguides in conjunction with a robust infrared electro-optic comb generator, as well as a chip-integrated microresonator comb. These results demonstrate a viable route towards astronomical precision spectroscopy in the ultraviolet and could contribute to unlock the full potential of next-generation ground-based and future space-based instruments. Here the authors demonstrate ultraviolet astronomical frequency combs, derived from the near-infrared domain via efficient harmonic generation in nanophotonic waveguides, to provide precision calibration to astronomical spectrographs for exoplanet science and precision cosmology. [ABSTRACT FROM AUTHOR]

Employee job satisfaction is an important attitudinal variable for many reasons, and due to the current shortage of workers, it may be even more critical in today's workplace. Job satisfaction is one of the most studied variables in the organizational behavior literature, mainly because researchers understand its impact on employee turnover and organizational effectiveness. The perception of workplace politics impacts job satisfaction. Most of the past research in the organizational behavior literature has found that employees generally perceive workplace politics negatively. However, there are differences in how employees view and react to organizational politics that are, at least partly, based on individual differences. The purpose of this study is to investigate the moderating effects of employee gender and age on the perceptions of organizational politics-job satisfaction relationship. A primary objective of this study is to provide further clarity on the effect of perceptions of politics in work reward decisions on specific job satisfaction facets for different age and gender groups. This study reports findings from a diverse group of 601 employees employed in more than a dozen organizations representing both the service and manufacturing sectors. We use hierarchical moderated regression analysis to test the study hypotheses to control for spurious variable contamination and isolate the study's main effects. The results support the hypothesis that employee perceptions of organizational politics have a different impact on job satisfaction for different gender and age groups. More specifically, results suggest that older employees are likely to be more negatively affected by perceptions of organizational politics than younger employees. Additionally, this study supports the notion that political decisions affect the job satisfaction of female employees more negatively than male employees in certain circumstances. [ABSTRACT FROM AUTHOR]

Geometric morphometrics (GMM) have been applied to understand morphological variation in biological structures. However, research studying cortical bone through geometric histomorphometrics (GHMM) is scarce. This research aims to develop a landmark‐based GHMM protocol to depict osteonal shape variation in the femoral diaphysis, exploring the role of age and biomechanics in bone microstructure. Proximal, midshaft, and distal anatomical segments from the femoral diaphysis of six individuals were assessed, with 864 secondary intact osteons from eight periosteal sampling areas being manually landmarked. Observer error was tested using Procrustes ANOVA. Average osteonal shape and anatomical segment‐specific variation were explored using principal component analysis. Osteon shape differences between segments were examined using canonical variate analysis (CVA). Sex differences were assessed through Procrustes ANOVA and discriminant function analysis (DFA). The impact of osteonal size on osteonal shape was investigated. High repeatability and reproducibility in osteon shape landmarking were reported. The average osteon shape captured was an elliptical structure, with PC1 reflecting more circular osteons. Significant differences in osteon shape were observed between proximal and distal segments according to CVA. Osteon shape differed between males and females, with DFA showing 52% cross‐validation accuracies. No effect of size on shape was reported. Osteonal shape variation observed in this study might be explained by the elderly nature of the sample as well as biomechanical and physiological mechanisms playing different roles along the femoral diaphysis. Although a larger sample is needed to corroborate these findings, this study contributes to the best of our knowledge on human microanatomy, proposing a novel GHMM approach. [ABSTRACT FROM AUTHOR]

The influence of pulping variables on the pulp and black liquor properties for a neutral sulphite semi-chemical pulping system was investigated in a pilot plant pulping setup situated at an industrial paper mill. Eucalyptus chips were used as raw material and the operating variables were Na2SO3 charge (8–18% w/w on oven-dry wood), Na2CO3 charge (0.5–3.0% w/w on oven-dry wood) and maximum cooking temperature (160–180 °C). Response surface methodology was used to parametrize empirical models to find the optimal conditions for maximizing the short-span compression strength index of the pulp. The derived regression models for the black liquor properties and the pulp hypo number had R2-adjusted values above 0.8 and p-values for overall significance below 0.05. The derived regression models for the handsheet strength properties had R2-adjusted values between 0.3 and 0.45 and p-values for overall significance either below 0.05 or between 0.05 and 0.1. The sulphite charge, followed by the carbonate charge, had the most notable effect on the evaluated properties with the effects of temperature being less significant. Optimization of the pilot plant system showed that the short-span compression strength index of the pulp could be maximized to 26.7 N m/g, using a sulphite charge of 9.4% (w/w on oven-dry wood) and a carbonate charge of 1.94% (w/w on oven-dry wood), similar to short-span compression strength indices typically achieved using other pulping processes. [ABSTRACT FROM AUTHOR]

Coevolution is often found in parasite–host interactions, but has not yet been described for hemiparasitic plants and their hosts. Root hemiparasites like Rhinanthus alectorolophus perform photosynthesis but also parasitize other plant species, some of which (e.g. Plantago lanceolata) may defend themselves against parasite attack by blocking the haustoria of the parasites. We grew seedlings of the hemiparasite R. alectorolophus and the potential host P. lanceolata from seven grassland sites in a factorial design. To detect differences in host defence, we also included hosts from two 'naïve' populations from regions where the parasite does not occur. R. alectorolophus grew consistently larger and had higher fitness with sympatric than with allopatric hosts, suggesting parasite adaptation to local host populations. Moreover, R. alectorolophus remained smallest with allopatric hosts from the same region and reached intermediate sizes with allopatric hosts from other regions or naïve hosts, suggesting host adaptation to parasites at the regional scale. Parasite presence reduced the size of the host plants already after four weeks, but only that of hosts with 'experience' of the parasite, suggesting an early host response. Follow‐up experiments confirmed that parasites attach to hosts already after four weeks and hosts respond by changing belowground allocation patterns. However, parasite roots did not preferentially grow towards sympatric hosts. Our results suggest that local adaptation to hosts can occur even in generalist parasites and does not require specialization on individual hosts. We discuss the role of potential mechanisms, including variation in chemical signalling (early) and in host defence (late effects). [ABSTRACT FROM AUTHOR]

Ground-based astronomy is unavoidably subject to the adverse effect of atmospheric turbulence, a.k.a. the seeing, which blurs the images and limits the achievable spatial resolution. For spectroscopic observations, it leads to slit or fibre-injection losses, since not all photons distributed over the extended seeing disc can be captured. These losses might have a very substantial impact on the overall efficiency of a spectrograph and are naturally highly variable. Assessing the fibre-injection losses requires accurate information about the image quality (IQ) delivered by the telescope to the instrument over the course of the observations, which, however, is often not directly available. ESPRESSO provides acquisition and field-stabilization images attached to the science data and thus offers the opportunity for a post-processing analysis. Here, we present a novel method to infer the IQ profile and fibre-injection losses from the integrated field-stabilization images, utilizing the spill-over light that does not get injected into the fibre. We validate these measurements against the IQ observed in the acquisition images and determine that our method delivers unbiased estimates with a scatter of 0.11 arcsec for the FWHM of the profile and |$15~{{\ \rm per\ cent}}$| in terms of fibre-injection losses. This compares favourably to the estimates derived from either the differential image motion monitor or the telescope guide probe sensors and therefore represents a valuable tool to characterize the instrument efficiency and to correct raw spectra for fibre-injection losses. [ABSTRACT FROM AUTHOR]

Background: Ex vivo normothermic machine perfusion (NMP) is a promising tool for assessing an isolated kidney prior to transplantation. However, there is no consensus on the perfusate's optimal oxygen‐carrying capacity to support renal function. To investigate the association of hemoglobin levels with renal function parameters, a retrospective analysis of isolated, normothermically, perfused porcine kidneys was performed. Methods: Between 2015 and 2021, a total of 228 kidneys underwent 4 h of NMP with perfusates that varied in hemoglobin levels. A generalized linear model was used to determine the association of hemoglobin levels with time‐weighted means of renal function markers, such as fractional sodium excretion (FENa) and creatinine clearance (CrCl). Stratified by baseline hemoglobin level (<4.5, 4.5–6, or >6 mmol/L), these markers were modeled over time using a generalized linear mixed‐effects model. All models were adjusted for potential confounders. Results: Until a hemoglobin level of around 5 mmol/L was reached, increasing hemoglobin levels were associated with superior FENa and CrCl. Thereafter, this association plateaued. When hemoglobin levels were categorized, hemoglobin <4.5 mmol/L was associated with worse renal function. Hemoglobin levels were neither significantly associated with proteinuria during NMP nor with ATP levels at the end of NMP. Hemoglobin levels >6 mmol/L showed no additional benefits in renal function. Conclusion: In conclusion, we found an association between baseline hemoglobin levels and superior renal function parameters, but not injury, during NMP of porcine kidneys. Furthermore, we show that performing a retrospective cohort study of preclinical data is feasible and able to answer additional questions, reducing the potential use of laboratory animals. [ABSTRACT FROM AUTHOR]

A quantum-light source that delivers photons with a high brightness and a high degree of entanglement is fundamental for the development of efficient entanglement-based quantum-key distribution systems. Among all possible candidates, epitaxial quantum dots are currently emerging as one of the brightest sources of highly entangled photons. However, the optimization of both brightness and entanglement currently requires different technologies that are difficult to combine in a scalable manner. In this work, we overcome this challenge by developing a novel device consisting of a quantum dot embedded in a circular Bragg resonator, in turn, integrated onto a micromachined piezoelectric actuator. The resonator engineers the light-matter interaction to empower extraction efficiencies up to 0.69(4). Simultaneously, the actuator manipulates strain fields that tune the quantum dot for the generation of entangled photons with corrected fidelities to a maximally entangled state up to 0.96(1). This hybrid technology has the potential to overcome the limitations of the key rates that plague QD-based entangled sources for entanglement-based quantum key distribution and entanglement-based quantum networks. [ABSTRACT FROM AUTHOR]

Motivation Acute kidney injury (AKI) is a syndrome that affects a large fraction of all critically ill patients, and early diagnosis to receive adequate treatment is as imperative as it is challenging to make early. Consequently, machine learning approaches have been developed to predict AKI ahead of time. However, the prevalence of AKI is often underestimated in state-of-the-art approaches, as they rely on an AKI event annotation solely based on creatinine, ignoring urine output.   We construct and evaluate early warning systems for AKI in a multi-disciplinary ICU setting, using the complete KDIGO definition of AKI. We propose several variants of gradient-boosted decision tree (GBDT)-based models, including a novel time-stacking based approach. A state-of-the-art LSTM-based model previously proposed for AKI prediction is used as a comparison, which was not specifically evaluated in ICU settings yet. Results We find that optimal performance is achieved by using GBDT with the time-based stacking technique (AUPRC = 65.7%, compared with the LSTM-based model's AUPRC = 62.6%), which is motivated by the high relevance of time since ICU admission for this task. Both models show mildly reduced performance in the limited training data setting, perform fairly across different subcohorts, and exhibit no issues in gender transfer.   Following the official KDIGO definition substantially increases the number of annotated AKI events. In our study GBDTs outperform LSTM models for AKI prediction. Generally, we find that both model types are robust in a variety of challenging settings arising for ICU data. Availability and implementation The code to reproduce the findings of our manuscript can be found at: https://github.com/ratschlab/AKI-EWS [ABSTRACT FROM AUTHOR]

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles. [ABSTRACT FROM AUTHOR]

Background: After posterior cruciate ligament reconstruction (PCLR), functional deficits at the knee can persist. It remains unclear if neighboring joints compensate for the knee during demanding activities of daily living. Purpose: To assess long-term alterations in lower limb mechanics in patients after PCLR. Study Design: Descriptive laboratory study. Methods: A total of 28 patients who had undergone single-bundle unilateral isolated or combined PCLR performed stair navigation, squat, sit-to-stand, and stand-to-sit tasks at 8.2 ± 2.2 years after surgery. Motion capture and force plates were used to collect kinematic and kinetic data. Then, 3-dimensional hip, knee, and ankle kinematic data of the reconstructed limb were compared with those of the contralateral limb using statistical parametric mapping. Results: Side-to-side differences at the knee were primarily found during upward-driven movements at 8 years after surgery. The reconstructed knee exhibited lower internal rotation during the initial loading phase of stair ascent versus the contralateral knee (P =.005). During the sit-to-stand task, higher flexion angles during the midcycle (P =.017) and lower external rotation angles (P =.049) were found in the reconstructed knee; sagittal knee (P =.001) and hip (P =.016) moments were lower in the reconstructed limb than the contralateral limb. In downward-driven movements, side-to-side differences were minimal at the knee but prominent at the ankle and hip: during stair descent, the reconstructed ankle exhibited lower dorsiflexion and lower external rotation during the midcycle versus the contralateral ankle (P =.006 and P =.040, respectively). Frontal hip moments in the reconstructed limb were higher than those in the contralateral limb during the stand-to-sit task (P =.010); during squats, sagittal hip angles in the reconstructed limb were higher than those in the contralateral limb (P <.001). Conclusion: Patients after PCLR exhibited compensations at the hip and ankle during downward-driven movements, such as stair descent, squats, and stand-to-sit. Conversely, residual long-term side-to-side differences at the knee were detected during upward-driven movements such as stair ascent and sit-to-stand. Clinical Relevance: After PCLR, side-to-side differences in biomechanical function were activity-dependent and occurred either at the knee or neighboring joints. When referring to the contralateral limb to assess knee function in the reconstructed limb, concentric, upward-driven movements should be prioritized. Compensations at the hip and ankle during downward-driven movements lead to biases in long-term functional assessments. [ABSTRACT FROM AUTHOR]

Achieving a truly accurate wavelength calibration of high-dispersion echelle spectrographs is a challenging task but crucially needed for certain science cases, e.g. to test for a possible variation of the fine-structure constant in quasar spectra. One of the spectrographs best suited for this mission is Very Large Telescope/Echelle SPectrograph for Rocky Exoplanets and Stable Spectroscopic Observation (ESPRESSO). Nevertheless, previous studies have identified significant discrepancies between the classical wavelength solutions and the one derived independently from the laser frequency comb. The dominant parts of these systematics were intra-order distortions, most-likely related to a deviation of the instrumental line-spread function from the assumed Gaussian shape. Here, we therefore present a study focused on a detailed modelling of the ESPRESSO instrumental line-spread function. We demonstrate that it is strongly asymmetric, non-Gaussian, different for the two slices and fibres, and varies significantly along the spectral orders. Incorporating the determined non-parametric model in the wavelength calibration process drastically improves the wavelength calibration accuracy, reducing the discrepancies between the two independent wavelength solutions from |$50\,\rm{m\,s^{-1}}$| to about |$10\, \rm{m\,s^{-1}}$|⁠. The most striking success is, however, that the different fibres and slices now provide fully consistent measurements with a scatter of just a couple m s−1. This demonstrates that the instrument-related systematics can be nearly eliminated over most of the spectral range by properly taking into account the complex shape of the instrumental line-spread function and paves the way for further optimizations of the wavelength calibration process. [ABSTRACT FROM AUTHOR]

Polarized |S|=0.99±0.01$| S | = 0.99 \pm 0.01$, and unpolarized |S|=0.03±0.01$| S | = 0.03 \pm 0.01$ emission from a single emitter embedded in a single, cylindrically symmetric device design is presented. The polarization stems from a position offset of the single emitter with respect to the cavity center, which breaks the cylindrical symmetry, and a position‐dependent coupling to the frequency degenerate eigenmodes of the resonator structure is shown. The experimental results are interpreted by using numerical simulations and by experimental mapping of the polarization‐resolved far‐field emission patterns. The findings can be generalized to any nanophotonic structure where two orthogonal eigenmodes are not fully spatially overlapping. [ABSTRACT FROM AUTHOR]

Primordial abundances of light elements are sensitive to the physics of the early Universe and can directly constrain cosmological quantities, such as the baryon-to-photon ratio |$\eta _{10}$|⁠ , the baryon density, and the number of neutrino families. Deuterium is especially suited for these studies: its primordial abundance is sensitive and monotonically dependent on |$\eta _{10}$|⁠ , allowing an independent measurement of the cosmic baryon density that can be compared, for instance, against the Planck satellite data. The primordial deuterium abundance can be measured in high H  i column density absorption systems towards distant quasars. We report here a new measurement, based on high-resolution ESPRESSO data, of the primordial D  i abundance of a system at redshift |$z \sim 3.572$|⁠ , towards PKS1937-101. Using only ESPRESSO data, we find a D /H ratio of |$2.638\pm 10^{-5}$|⁠ , while including the available UVES data improves the precision, leading to a ratio of |$2.608 \pm 10^{-5}$|⁠. The results of this analysis agree with those of the most precise existing measurements. We find that the relatively low column density of this system (⁠|$\log {N_{\rm H_I}/ {\rm cm}^{-2}}\sim 18$|⁠) introduces modelling uncertainties, which become the main contributor to the error budget. [ABSTRACT FROM AUTHOR]

The gravitationally lensed quasar J014516.6-094517 at z  = 2.719 has been observed with the ESPRESSO instrument at the ESO VLT to obtain high-fidelity spectra of the two images A and B with a resolving power R  = 70 000. At the redshifts under investigation (2.1 ≲ z ≲ 2.7), the Lyman forests along the two sightlines are separated by sub-kiloparsec physical distances and exhibit a strong correlation. We find that the two forests are indistinguishable at the present level of signal-to-noise ratio and do not show any global velocity shift, with the cross-correlation peaking at Δ v  = 12 ± 48 |$\rm m~s^{-1}$|⁠. The distribution of the difference in velocity of individual Ly α features is compatible with a null average and a mean absolute deviation of 930 |$\rm m~s^{-1}$|⁠. Significant differences in N H  i column density are not detected, putting a limit to the RMS fluctuation in the baryon density on ≲1 proper kpc scales of Δρ/ρ ≲ 3 per cent. On the other hand, metal lines show significant differences both in velocity structure and in column density. A toy model shows that the difference in velocity of the metal features between the two sightlines is compatible with the motions of the baryonic component associated with dark matter haloes of typical mass M ≃ 2 × 1010 M⊙, also compatible with the observed incidence of the metal systems. The present observations confirm the feasibility of the Sandage test of the cosmic redshift drift with high-fidelity spectroscopy of the Lyman forest of distant, bright quasars, but also provide an element of caution about the intrinsic noise associated with the usage of metal features for the same purpose. [ABSTRACT FROM AUTHOR]

Objectives: To attain a collective expert opinion on the use of air powder waterjet technology (APWT) with erythritol and glycine powders in the prophylaxis and therapy of periodontal and peri‐implant diseases. Material and Methods: In the first step, a modified one‐round online Delphi survey including 44 five‐point Likert scale questions was conducted among a group of 10 expert clinicians and researchers with thorough knowledge and experience in this topic. In the second step, the single questions and the survey results were discussed during a meeting, and consensus statements were formulated, respectively. Results: An agreement was reached on most items, especially opinions supporting glycine and erythritol powders as favorable with respect to efficiency, safety, and comfort. More scientific evidence is needed to support the improvement in clinical attachment on teeth and implants, especially when APWT with erythritol is used. In addition, APWT needs more long‐term evaluation and studies in terms of microbiome/microbiological effects as well as effects on the inflammatory response on natural teeth and implants, also in light of a guided biofilm therapy concept. Conclusions: In line with the expert opinions and supported by the evidence, it was concluded that the use of APWT with erythritol and glycine powders in nonsurgical periodontal and peri‐implant therapy and prophylaxis is patient compliant and efficient. [ABSTRACT FROM AUTHOR]

The nature of the hydrogen substructure of a deuterated and deuterium chloride (DCI)-doped ice VI sample after cooling at 1.8 GPa has been a topic of recent interest—especially because the novel ice polymorph ice XIX was discovered in the course of such studies. We here investigate deuterated samples containing 5% H2O using Raman spectroscopy to probe for transitions associated with rearrangement of D-atoms in ice XIX. The protocol involving heating at subambient pressure (10 mbar) in this study follows closely the one used in our earlier neutron diffraction study. Heating of ice XIX induces a complex cascade of processes involving both ordering and disordering of D atoms. Our Raman spectra demonstrate that the transition sequence is ice XIX → ice VI‡ → ice XV, in accordance with our earlier neutron diffraction result. First signs for ice XIX decay are evident at 100 K, while ice XV build-up is seen only at 108 K and above. Between 100 and 108 K, a transiently disordered D-substructure appears, where at 108 K, ice VI‡ forms from ice XIX and simultaneously decays to produce ice XV—thereby establishing a dynamic equilibrium. Using isothermal, time-resolved Raman spectroscopy in real time, we here determine rate constants, Avrami exponents, and activation energies for both slow processes, ice XIX decay and ice XV build-up. The first transition in this sequence, ice XIX decay, is faster than the second transition, ice XV build-up, so that ice VI‡ accumulates. On the basis of the Johnson–Mehl–Avrami–Kolmogorov data obtained from the isothermal Raman experiment, we additionally report kinetic models for the development of fractions of ices XIX, XV, and VI‡ in non-isothermal heating experiments at different heating rates. These models consider the two coupled first-order transitions as separated processes, where the phase fractions are calculated for incrementally small temperature (or time) steps. These models compare favorably with our previous observations for slowly or rapidly heated ice XIX samples, such as in calorimetry or neutron diffraction experiments. [ABSTRACT FROM AUTHOR]

Many factors influence well-being and health in everyday life. While people are aware of traffic delays or continuous work stress, other factors influence the state of the body on a subconscious level. The built environment subconsciously influences human physiology during every second of life, which has a cumulative long-term effect. The idea of biophilic design identifies the importance of natural elements implemented in architectural structures to improve the occupants' health and well-being. This paper measures the impact of biophilic design on positive emotions and productivity in two separate but conceptually related pilot studies that apply novel approaches: (a) facial emotion recognition (FER) with residual masking networks and (b) sentiment detection using Large Language Models. The first study measures the emotions of people when confronted with images of different kinds of architecture, via FER and via a user survey. We find clear trends for emotions detected by FER and significant evidence for self-stated emotions that architecture implementing biophilic design evokes more positive emotions. The second study measures the influence of natural elements on productivity and team engagement. The findings show that natural elements in the surroundings do influence productivity and sentiment positively. As the sample size of subjects, especially for the second study, was relatively small, future research will need to apply these ideas in a larger setup to acquire further evidence for the importance of biophilic design for human well-being and health. [ABSTRACT FROM AUTHOR]

Invariant solutions of the Navier--Stokes equations play an important role in the spatiotemporally chaotic dynamics of turbulent shear flows. Despite the significance of these solutions, their identification remains a computational challenge, rendering many solutions inaccessible and thus hindering progress towards a dynamical description of turbulence in terms of invariant solutions. We compute equilibria of three-dimensional wall-bounded shear flows using an adjoint-based matrix-free variational approach. To address the challenge of computing pressure in the presence of solid walls, we develop a formulation that circumvents the explicit construction of pressure and instead employs the influence matrix method. Together with a data-driven convergence acceleration technique based on dynamic mode decomposition, this yields a practically feasible alternative to state-of-the-art Newton methods for converging equilibrium solutions. We compute multiple equilibria of plane Couette flow starting from inaccurate guesses extracted from a turbulent time series. The variational method outperforms Newton(-hookstep) iterations in converging successfully from poor initial guesses, suggesting a larger convergence radius. [ABSTRACT FROM AUTHOR]

Tight gas sandstone reservoirs play an important role in the field of exploration and development of unconventional oil/gas resources. However, these reservoirs typically exhibit low-porosity and poor-permeability, with pore structures of strong heterogeneity comprising connected and isolated pores. The traditional rock physics models (such as the Gassmann model) are established under the assumption of fully connected pores, which cannot reasonably describe the complexity in tight reservoirs. In this regard, this work proposes a rock physics modeling approach aimed at tight sandstone reservoirs based on a reformulated Xu–White model. Specifically, the differential effective medium model and Xu–White model are combined to analyze the influences of isolated pores on the dry rock skeleton. To characterize the general effects due to the different pore types on rock elastic moduli, the volume content of connected pores is defined as a pore-connectivity parameter. The simulated annealing algorithm is applied to invert the parameter, which is treated as a weighting coefficient for correcting the wet rock elastic moduli, thereby improving the precision of rock physics modeling. The proposed approach is tested and verified by using the log data of the work area of Sichuan Basin, West China. The result shows that, compared with the conventional method, the P- and S-wave velocities predicted by the proposed method are consistent with the log data. In addition to the inversion results of the conventional petrophysical parameters, the inverted pore-connectivity parameter can be a good auxiliary attribute that assists locating potential targets for tight gas sandstone reservoirs. [ABSTRACT FROM AUTHOR]

Background: SHANKs are major scaffolding proteins at postsynaptic densities (PSDs) in the central nervous system. Mutations in all three family members have been associated with neurodevelopmental disorders such as autism spectrum disorders (ASDs). Despite the pathophysiological importance of SHANK2 and SHANK3 mutations in humans, research on the expression of these proteins is mostly based on rodent model organisms. Results: In the present study, cellular and neuropil SHANK2 expression was analyzed by immunofluorescence (IF) staining of post mortem human brain tissue from four male individuals (19 brain regions). Mouse brains were analyzed in comparison to evaluate the degree of phylogenetic conservation. Furthermore, SHANK2 and SHANK3 isoform patterns were compared in human and mouse brain lysates. While isoform expression and subcellular distribution were largely conserved, differences in neuropil levels of SHANK2 were found by IF staining: Maximum expression was concordantly measured in the cerebellum; however, higher SHANK2 expression was detected in the human brainstem and thalamus when compared to mice. One of the lowest SHANK2 levels was found in the human amygdala, a moderately expressing region in mouse. Quantification of SHANK3 IF in mouse brains unveiled a distribution comparable to humans. Conclusions: In summary, these data show that the overall expression pattern of SHANK is largely conserved in defined brain regions; however, differences do exist, which need to be considered in the translation of rodent studies. The summarized expression patterns of SHANK2 and SHANK3 should serve as a reference for future studies. [ABSTRACT FROM AUTHOR]

Bis(trifluoromethylated)benziodoxoles (Bx) are broadly used cyclic hypervalent iodine reagents due to their stability and unique chemical properties. However, current methods to access them require several steps and long reaction times, making their synthesis tedious. Herein, a direct one-pot synthesis of bis(trifluoromethylated) Bx reagents from iodine(I) precursors is reported, enabling the synthesis of functionalized reagents. [ABSTRACT FROM AUTHOR]

The thalamus acts as an interface between the periphery and the cortex, with nearly every sensory modality processing information in the thalamocortical circuit. Despite well-established thalamic nuclei for visual, auditory, and tactile modalities, the key thalamic nuclei responsible for innocuous thermosensation remains under debate. Thermosensory information is first transduced by thermoreceptors located in the skin and then processed in the spinal cord. Temperature information is then transmitted to the brain through multiple spinal projection pathways including the spinothalamic tract and the spinoparabrachial tract. While there are fundamental studies of thermal transduction via thermosensitive channels in primary sensory afferents, thermal representation in the spinal projection neurons, and encoding of temperature in the primary cortical targets, comparatively little is known about the intermediate stage of processing in the thalamus. Multiple thalamic nuclei have been implicated in thermal encoding, each with a corresponding cortical target, but without a consensus on the role of each pathway. Here, we review a combination of anatomy, physiology, and behavioral studies across multiple animal models to characterize the thalamic representation of temperature in two proposed thermosensory information streams. [ABSTRACT FROM AUTHOR]

A clear recommendation regarding treatment strategy of fragility fractures of the pelvic ring is missing. The most typical fracture pattern is a lateral compression type injury with non-displaced fractures of the anterior pubic rami and a unilateral os sacrum fracture (FFP II). We hypothesized that operative treatment would be superior to conservative treatment. From October 2017 to April 2020, a randomized prospective non-blinded trial with n = 39 patients was carried out. Two arms with 17 operative versus 22 conservative cases were created. Inclusion criteria were a posterior pelvic ring fracture FFP type II, age over 60 years and acute fracture (< 3 weeks). Barthel index, pain level (VAS), quality of life (EQ-5D-3L), and Tinetti–Gait Test were determined on admission, at discharge, and after 3, 6, 12 and 24 months. Median follow-up was 12.9 months. The Barthel index (= 0.325), VAS (p = 0.711), quality of life (p = 0.824), and Tinetti–Gait Test (p = 0.913) showed no significant differences between the two groups after 12 months. Two patients switched from the conservative to the operative arm due to persistent immobilization and pain. The one-year mortality rate showed no significant difference (p = 0.175). Our hypothesis that surgical treatment is superior was refuted. No significant benefit was shown in terms of quality of life, mortality and pain levels. The results suggest a more differentiated treatment approach in the future, with initial conservative treatment preferred. A larger multi-center trial is required to confirm these findings. Trial registration: The study was retrospectively registered with the German Clinical Trials Registry (DRKS00013703) on 10/12/2018. [ABSTRACT FROM AUTHOR]

The natural product class of the sorbicillinoids is composed of structurally diverse molecules with many strong, biomedically relevant biological activities. Owing to their complex structures, the synthesis of sorbicillinoids is a challenging task. Here we show the first total synthesis of the fungal sorbicillinoids spirosorbicillinols A–C. The convergent route comprises the chemo-enzymatic transformation of sorbicillin to the highly reactive sorbicillinol and the assembly of scytolide and isomers starting from shikimic and quinic acid analogs. The key step in the total synthesis is the fusion of both building blocks in a Diels-Alder cycloaddition leading to the straightforward formation of the characteristic sorbicillinoid bicyclo[2.2.2]octane backbone. This work provides unifying access to all natural spirosorbicillinols and unnatural diastereomers. Spirosorbicillinols A–C are fungal natural products that display various biological properties, but their total synthesis has yet to be accomplished. Here, the authors report the total synthesis of spirosorbicillinols A–C based on a chemo-enzymatic transformation of sorbicillin into sorbicillinol, which is fused to synthetically prepared scytolide and isomers by a Diels-Alder cycloaddition reaction. [ABSTRACT FROM AUTHOR]

Background: Phelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients. Results: CSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer's disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer's disease. Conclusions: In summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof. [ABSTRACT FROM AUTHOR]

Fractures can greatly impact fluid flow and pore pressure distribution in the upper crust. By conducting borehole hydraulic experiments, we can determine the ability of fractures to transport fluids and affect pressure diffusion under in situ conditions. We performed a series of periodic hydraulic tests in a borehole at the Bedretto Underground Laboratory for Geosciences and Geoenergies (Switzerland). We investigated the period‐ and pressure‐dependent response of a fractured granite by controlling the flow rate of harmonic and non‐harmonic oscillations, covering a wide range of periods as well as mean‐ and amplitude‐pressure values. By analyzing the phase and amplitude relation between the flow rate and fluid pressure in the injection interval, we found that the intersected fracture zone exhibits a period‐dependent hydraulic response close to radial flow perturbed by fracture‐related hydromechanical coupling effects. The main features of the interval's hydraulic response were reproduced by an uncoupled diffusion solution for radial flow, which was used to derive apparent hydraulic properties. The largest deviations from this model occur for the phase shifts and correlate with the pressure amplitude. This non‐linear expression of hydromechanical coupling associated with deformable fractures was interpreted in terms of a pressure‐dependent effective compliance of the fractures that affects their effective storativity. The period dependence is likely related to the spatial heterogeneity expected in fractured rocks and the varying sensitivity of the hydraulic response for different periods. Accounting for these effects is necessary for a correct hydraulic characterization in fractured environments and is valuable for inferring fracture mechanical behavior. Plain Language Summary: Fractures govern the hydraulic and mechanical behavior of rocks, and their characterization is crucial for understanding natural and anthropogenically induced processes involving stress and fluid pressure changes in fractured environments. Periodic pumping tests are specialized experiments used to quantify the ability of fractures to transport fluids and to affect pressure distribution in the subsurface. These experiments consist of recording the pressure response of a borehole interval to an injected oscillatory flow. We performed periodic pumping tests on fractures intersecting a borehole and analyzed their response to different testing parameters, such as, the period and amplitude of the oscillations and the type of oscillation. We found that the pressure‐flow rate relation can be fairly well explained by a simple model for porous rocks that ignores any complexity associated with the presence of fractures. Nevertheless, notable effects that cannot be explained by the model are found to be correlated with the period and amplitude of the oscillations. Capturing the period dependence is useful for characterizing heterogeneities away from the borehole, while the oscillation amplitude dependence shows the impact of the deformability of fractures exposed to pressure variations. Future modeling and experimental techniques should consider these findings to improve interpretation methods. Key Points: We conducted periodic pumping tests on fractures intersecting a borehole varying their period and the mean‐ and amplitude‐pressure valuesThe observed flow rate versus pressure behavior can largely be reproduced by an uncoupled diffusion solution for radial flowWe observed a dependence of the hydraulic response on the period and on the pressure amplitude likely related to fracture deformation [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a fatal and incurable neurodegenerative disease that mainly affects the neurons of the motor system. Despite the increasing understanding of its genetic components, their biological meanings are still poorly understood. Indeed, it is still not clear to which extent the pathological features associated with amyotrophic lateral sclerosis are commonly shared by the different genes causally linked to this disorder. To address this point, we combined multiomics analysis covering the transcriptional, epigenetic and mutational aspects of heterogenous human induced pluripotent stem cell-derived C9orf72-, TARDBP- , SOD1- and FUS- mutant motor neurons as well as datasets from patients' biopsies. We identified a common signature, converging towards increased stress and synaptic abnormalities, which reflects a unifying transcriptional program in amyotrophic lateral sclerosis despite the specific profiles due to the underlying pathogenic gene. In addition, whole genome bisulphite sequencing linked the altered gene expression observed in mutant cells to their methylation profile, highlighting deep epigenetic alterations as part of the abnormal transcriptional signatures linked to amyotrophic lateral sclerosis. We then applied multi-layer deep machine-learning to integrate publicly available blood and spinal cord transcriptomes and found a statistically significant correlation between their top predictor gene sets, which were significantly enriched in toll-like receptor signalling. Notably, the overrepresentation of this biological term also correlated with the transcriptional signature identified in mutant human induced pluripotent stem cell-derived motor neurons, highlighting novel insights into amyotrophic lateral sclerosis marker genes in a tissue-independent manner. Finally, using whole genome sequencing in combination with deep learning, we generated the first mutational signature for amyotrophic lateral sclerosis and defined a specific genomic profile for this disease, which is significantly correlated to ageing signatures, hinting at age as a major player in amyotrophic lateral sclerosis. This work describes innovative methodological approaches for the identification of disease signatures through the combination of multiomics analysis and provides novel knowledge on the pathological convergencies defining amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

In search and rescue missions, teleoperated rovers equipped with sensor technology are deployed into harsh environments to search for targets. To support the search task, unimodal/multimodal cues can be presented via visual, acoustic and/or haptic channels. However, human operators often perform the search task in parallel with the driving task, which can cause interference of attentional resources based on multiple resource theory. Navigating corners can be a particularly challenging aspect of remote driving, as described with the Cornering Law. Therefore, search cues should not interfere with cornering. The present research explores how unimodal/multimodal search cues affect cornering performance, with typical communication delays of 50 ms and 500 ms. One-hundred thirty-one participants, distributed into two delay groups, performed a target search task with unimodal/multimodal search cues. Search cues did not interfere with cornering performance with 50 ms delays. For 500 ms delays, search cues presented via the haptic channel significantly interfered with the driving task. Practitioner summary: Teleoperated rovers can support search and rescue missions. Search cues may assist the human operator, but they may also interfere with the task of driving. The study examined interference of unimodal and multimodal search cues. Haptic cues should not be implemented for systems with a delay of 500 ms or more. [ABSTRACT FROM AUTHOR]

Background: Phelan–McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic-like behaviors and is primarily caused by haploinsufficiency of SHANK3 gene. Currently, there is no specific treatment for PMS, highlighting the need for a better understanding of SHANK3 functions and the underlying pathophysiological mechanisms in the brain. We hypothesize that SHANK3 haploinsufficiency may lead to alterations in the inhibitory system, which could be linked to the excitatory/inhibitory imbalance observed in models of autism spectrum disorder (ASD). Investigation of these neuropathological features may shed light on the pathogenesis of PMS and potential therapeutic interventions. Methods: We recorded local field potentials and visual evoked responses in the visual cortex of Shank3∆11−/− mice. Then, to understand the impact of Shank3 in inhibitory neurons, we generated Pv-cre+/−Shank3Fl/Wt conditional mice, in which Shank3 was deleted in parvalbumin-positive neurons. We characterized the phenotype of this murine model and we compared this phenotype before and after ganaxolone administration. Results: We found, in the primary visual cortex, an alteration of the gain control of Shank3 KO compared with Wt mice, indicating a deficit of inhibition on pyramidal neurons. This alteration was rescued after the potentiation of GABAA receptor activity by Midazolam. Behavioral analysis showed an impairment in grooming, memory, and motor coordination of Pv-cre+/−Shank3Fl/Wt compared with Pv-cre+/−Shank3Wt/Wt mice. These deficits were rescued with ganaxolone, a positive modulator of GABAA receptors. Furthermore, we demonstrated that treatment with ganaxolone also ameliorated evocative memory deficits and repetitive behavior of Shank3 KO mice. Limitations: Despite the significant findings of our study, some limitations remain. Firstly, the neurobiological mechanisms underlying the link between Shank3 deletion in PV neurons and behavioral alterations need further investigation. Additionally, the impact of Shank3 on other classes of inhibitory neurons requires further exploration. Finally, the pharmacological activity of ganaxolone needs further characterization to improve our understanding of its potential therapeutic effects. Conclusions: Our study provides evidence that Shank3 deletion leads to an alteration in inhibitory feedback on cortical pyramidal neurons, resulting in cortical hyperexcitability and ASD-like behavioral problems. Specifically, cell type-specific deletion of Shank3 in PV neurons was associated with these behavioral deficits. Our findings suggest that ganaxolone may be a potential pharmacological approach for treating PMS, as it was able to rescue the behavioral deficits in Shank3 KO mice. Overall, our study highlights the importance of investigating the role of inhibitory neurons and potential therapeutic interventions in neurodevelopmental disorders such as PMS. [ABSTRACT FROM AUTHOR]

It has recently been speculated that long-time average quantities of hyperchaotic dissipative systems may be approximated by weighted sums over unstable invariant tori embedded in the attractor, analogous to equivalent sums over periodic orbits, which are inspired by the rigorous periodic orbit theory and which have shown much promise in fluid dynamics. Using a new numerical method for converging unstable invariant two-tori in a chaotic partial differential equation (PDE), and exploiting symmetry breaking of relative periodic orbits to detect those tori, we identify many quasiperiodic, unstable, invariant two-torus solutions of a modified Kuramoto–Sivashinsky equation. The set of tori covers significant parts of the chaotic attractor and weighted averages of the properties of the tori—with weights computed based on their respective stability eigenvalues—approximate average quantities for the chaotic dynamics. These results are a step toward exploiting higher-dimensional invariant sets to describe general hyperchaotic systems, including dissipative spatiotemporally chaotic PDEs. [ABSTRACT FROM AUTHOR]

The quantizer problem is a tessellation optimization problem where point configurations are identified such that the Voronoi cells minimize the second moment of the volume distribution. While the ground state (optimal state) in 3D is almost certainly the body-centered cubic lattice, disordered and effectively hyperuniform states with energies very close to the ground state exist that result as stable states in an evolution through the geometric Lloyd's algorithm [M. A. Klatt et al. Nat. Commun. 10, 811 (2019)]. When considered as a statistical mechanics problem at finite temperature, the same system has been termed the "Voronoi liquid" by Ruscher, Baschnagel, and Farago [Europhys. Lett. 112, 66003 (2015)]. Here, we investigate the cooling behavior of the Voronoi liquid with a particular view to the stability of the effectively hyperuniform disordered state. As a confirmation of the results by Ruscher et al., we observe, by both molecular dynamics and Monte Carlo simulations, that upon slow quasi-static equilibrium cooling, the Voronoi liquid crystallizes from a disordered configuration into the body-centered cubic configuration. By contrast, upon sufficiently fast non-equilibrium cooling (and not just in the limit of a maximally fast quench), the Voronoi liquid adopts similar states as the effectively hyperuniform inherent structures identified by Klatt et al. and prevents the ordering transition into a body-centered cubic ordered structure. This result is in line with the geometric intuition that the geometric Lloyd's algorithm corresponds to a type of fast quench. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is mainly characterized by the degeneration of corticospinal neurons and spinal α-motoneurons; vulnerable cells display prominent pTDP-43 inclusions. Evidence gathered from genetics, murine models, and iPSC-derived neurons point to the early involvement of synapses in the disease course and their crucial role in the pathogenic cascade. However, pathology studies, with specimens from large post-mortem cohorts, mapping the pattern of synaptic disturbances over clinical and neuropathological hallmarks of disease progression, are currently not available. Thus, the appearance and progression of synaptic degeneration in human ALS patients are currently not known, preventing a full validation of the murine and in vitro models. Here, we investigated the loss of synaptophysin-positive terminals in cervical, thoracic, and lumbar spinal cord samples from a retrospective cohort of n = 33 ALS patients and n = 8 healthy controls, and we correlated the loss of synapses against clinicodemographic features and neuropathological ALS stage. We found that, although dorsal and intermediate spinal cord laminae do not lose synapses, ALS patients displayed a substantial but variable loss of synapses in the ventral horn of lumbar and cervical spinal cord. The amount of synaptic loss was predicted by disease duration, by the clinical site of onset, and by the loss of α-motoneurons, although not by the fraction of pTDP-43-immunopositive α-motoneurons. Taken together, our findings validate the synaptic pathology observed in other models and suggest that pathogenic pathways unfolding in the spinal microenvironment are critical to the progressive disassembly of local synaptic connectivity. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2−/− mice were protected from age-related OA development. Taken together, the TLR2–NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA. [ABSTRACT FROM AUTHOR]

One approach for describing spatiotemporal chaos is to study the unstable invariant sets embedded in the chaotic attractor of the system. While equilibria, periodic orbits, and invariant tori can be computed using existing methods, the numerical identification of heteroclinic and homoclinic connections between them remains challenging. We propose a robust matrix-free variational method for computing connecting orbits between equilibrium solutions. Instead of a common shooting-based approach, we view the identification of a connecting orbit as a minimization problem in the space of smooth curves in the state space that connect the two equilibria. In this approach, the deviation of a connecting curve from an integral curve of the vector field is penalized by a non-negative cost function. Minimization of the cost function deforms a trial curve until, at a global minimum, a connecting orbit is obtained. The method has no limitation on the dimension of the unstable manifold at the origin equilibrium and does not suffer from exponential error amplification associated with time-marching a chaotic system. Owing to adjoint-based minimization techniques, no Jacobian matrices need to be constructed. Therefore, the memory requirement scales linearly with the size of the problem, allowing the method to be applied to high-dimensional dynamical systems. The robustness of the method is demonstrated for the one-dimensional Kuramoto–Sivashinsky equation. [ABSTRACT FROM AUTHOR]

We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (−)‐zampanolide (ZMP). These analogs were derived from 13‐desmethylene‐(−)‐zampanolide (DM‐ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67–95 % yield) and a stereoselective aza‐aldol reaction with an (S)‐BINOL‐derived sorbamide transfer complex, to establish the C(20) stereocenter (24–71 % yield). As the sole exception, for the 5‐desmethyl macrocycle, ring‐closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. All modifications led to reduced cellular activity and lowered microtubule‐binding affinity compared to DM‐ZMP, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC50 values for cancer cell growth inhibition varied between 5 and 133 nM, compared to 1–12 nM for DM‐ZMP. Reduction of the enone double bond led to a several hundred‐fold loss in growth inhibition. The cellular potency of 2,3‐dihydro‐13‐desmethylene zampanolide, as the most potent analog identified, remained within a ninefold range of that of DM‐ZMP. [ABSTRACT FROM AUTHOR]

Sharing healthcare data is increasingly essential for developing data-driven improvements in patient care at the Intensive Care Unit (ICU). However, it is also very challenging under the strict privacy legislation of the European Union (EU). Therefore, we explored four successful open ICU healthcare databases to determine how open healthcare data can be shared appropriately in the EU. A questionnaire was constructed based on the Delphi method. Then, follow-up questions were discussed with experts from the four databases. These experts encountered similar challenges and regarded ethical and legal aspects to be the most challenging. Based on the approaches of the databases, expert opinion, and literature research, we outline four distinct approaches to openly sharing healthcare data, each with varying implications regarding data security, ease of use, sustainability, and implementability. Ultimately, we formulate seven recommendations for sharing open healthcare data to guide future initiatives in sharing open healthcare data to improve patient care and advance healthcare. [ABSTRACT FROM AUTHOR]

Background: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. Methods: We have used a Shank2−/− mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. Results: We determined that Shank2−/− mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2−/− mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2−/− mice. Limitations: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. Conclusion: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease characterized by sustained loss of neuromuscular junctions, degenerating corticospinal motoneurons and rapidly progressing muscle paralysis. Motoneurons have unique features, essentially a highly polarized, lengthy architecture of axons, posing a considerable challenge for maintaining long-range trafficking routes for organelles, cargo, mRNA and secretion with a high energy effort to serve crucial neuronal functions. Impaired intracellular pathways implicated in ALS pathology comprise RNA metabolism, cytoplasmic protein aggregation, cytoskeletal integrity for organelle trafficking and maintenance of mitochondrial morphology and function, cumulatively leading to neurodegeneration. Current drug treatments only have marginal effects on survival, thereby calling for alternative ALS therapies. Exposure to magnetic fields, e.g., transcranial magnetic stimulations (TMS) on the central nervous system (CNS), has been broadly explored over the past 20 years to investigate and improve physical and mental activities through stimulated excitability as well as neuronal plasticity. However, studies of magnetic treatments on the peripheral nervous system are still scarce. Thus, we investigated the therapeutic potential of low frequency alternating current magnetic fields on cultured spinal motoneurons derived from induced pluripotent stem cells of FUS-ALS patients and healthy persons. We report a remarkable restoration induced by magnetic stimulation on axonal trafficking of mitochondria and lysosomes and axonal regenerative sprouting after axotomy in FUS-ALS in vitro without obvious harmful effects on diseased and healthy neurons. These beneficial effects seem to derive from improved microtubule integrity. Thus, our study suggests the therapeutic potential of magnetic stimulations in ALS, which awaits further exploration and validation in future long-term in vivo studies. [ABSTRACT FROM AUTHOR]

The Hot Disk method is a transient measurement method for the determination of thermal properties like the thermal conductivity, which is characterized by advantages such as a short measurement time or a low effort for the sample preparation. However, some difficulties related to measurements at elevated temperatures, which could be attributed to inaccuracies of the Temperature Coefficients of Resistance (TCRs), have been pointed out in the past. This paper presents a detailed investigation of the Hot Disk method for the determination of the thermal conductivity and contributes to a further improvement of its measurement accuracy. Subsequent to an extensive literature review of available reference materials for the thermal conductivity, measurements up to 750 °C were carried out with a Hot Disk TPS 2500 S with various Kapton and Mica sensors using three reference materials (Silcal 1100, Pyroceram 9606, Inconel 600). While room-temperature measurements confirmed the suitability of the reference samples as well as the independence of the measured thermal conductivity from the sensor, temperature-dependent measurements allowed the verification of the accuracy of the given TCRs. A set of optimized TCRs is proposed, with which the thermal conductivity of all three reference materials could be determined with an accuracy of 2 %. Furthermore, the measurement uncertainty of ± 5 % specified by the manufacturer could be confirmed. Hence, with the newly suggested TCRs, the Hot Disk method enables the determination of the thermal properties of a variety of materials even at high temperatures with high accuracy. [ABSTRACT FROM AUTHOR]

We propose a variational inference-based framework for training a Gaussian process regression model subject to censored observational data. Data censoring is a typical problem encountered during the data gathering procedure and requires specialized techniques to perform inference since the resulting probabilistic models are typically analytically intractable. In this article we exploit the variational sparse Gaussian process inducing variable framework and local variational methods to compute an analytically tractable lower bound on the true log marginal likelihood of the probabilistic model which can be used to perform Bayesian model training and inference. We demonstrate the proposed framework on synthetically-produced, noise-corrupted observational data, as well as on a real-world data set, subject to artificial censoring. The resulting predictions are comparable to existing methods to account for data censoring, but provides a significant reduction in computational cost. [ABSTRACT FROM AUTHOR]

Damage to plant communities imposed by insect herbivores generally decreases from low to high latitudes. This decrease is routinely attributed to declines in herbivore abundance and/or diversity, whereas latitudinal changes in per capita food consumption remain virtually unknown. Here, we tested the hypothesis that the lifetime food consumption by a herbivore individual decreases from low to high latitudes due to a temperature‐driven decrease in metabolic expenses. From 2016 to 2019, we explored latitudinal changes in multiple characteristics of linear (gallery) mines made by larvae of the pygmy moth, Stigmella lapponica, in leaves of downy birch, Betula pubescens. The mined leaves were larger than intact leaves at the southern end of our latitudinal gradient (at 60°N) but smaller than intact leaves at its northern end (at 69°N), suggesting that female oviposition preference changes with latitude. No latitudinal changes were observed in larval size, mine length or area, and in per capita food consumption, but the larval feeding efficiency (quantified as the ratio between larval size and mine size) increased with latitude. Consequently, S. lapponica larvae consumed less foliar biomass at higher latitudes than at lower latitudes to reach the same size. Based on space‐for‐time substitution, we suggest that climate warming will increase metabolic expenses of insect herbivores with uncertain consequences for plant–herbivore interactions. [ABSTRACT FROM AUTHOR]