julilili42/papers huggingface dataset:
Outcomes in Critically Ill Patients Sedated with Intravenous Lormetazepam or Midazolam: A Retrospective Cohort Study
2021-09-10

The benzodiazepine, midazolam, is one of the most frequently used sedatives in intensive care medicine, but it has an unfavorable pharmacokinetic profile when continuously applied. As a consequence, patients are frequently prolonged and more deeply sedated than intended. Due to its distinct pharmacological features, including a cytochrome P450-independent metabolization, intravenous lormetazepam might be clinically advantageous compared to midazolam. In this retrospective cohort study, we compared patients who received either intravenous lormetazepam or midazolam with respect to their survival and sedation characteristics. The cohort included 3314 mechanically ventilated, critically ill patients that received one of the two drugs in a tertiary medical center in Germany between 2006 and 2018. A Cox proportional hazards model with mortality as outcome and APACHE II, age, gender, and admission mode as covariates revealed a hazard ratio of 1.75 [95% CI 1.46–2.09; p &lt; 0.001] for in-hospital mortality associated with the use of midazolam. After additionally adjusting for sedation intensity, the HR became 1.04 [95% CI 0.83–1.31; p = 0.97]. Thus, we concluded that excessive sedation occurs more frequently in critically ill patients treated with midazolam than in patients treated with lormetazepam. These findings require further investigation in prospective trials to assess if lormetazepam, due to its ability to maintain light sedation, might be favorable over other benzodiazepines for sedation in the ICU.
Learning Speech-driven 3D Conversational Gestures from Video
2021-09-10

We propose the first approach to automatically and jointly synthesize both the synchronous 3D conversational body and hand gestures, as well as 3D face and head animations, of a virtual character from speech input. Our algorithm uses a CNN architecture that leverages the inherent correlation between facial expression and hand gestures. Synthesis of conversational body gestures is a multi-modal problem since many similar gestures can plausibly accompany the same input speech. To synthesize plausible body gestures in this setting, we train a Generative Adversarial Network (GAN) based model that measures the plausibility of the generated sequences of 3D body motion when paired with the input audio features. We also contribute a new way to create a large corpus of more than 33 hours of annotated body, hand, and face data from in-the-wild videos of talking people. To this end, we apply state-of-the-art monocular approaches for 3D body and hand pose estimation as well as dense 3D face performance capture to the video corpus. In this way, we can train on orders of magnitude more data than previous algorithms that resort to complex in-studio motion capture solutions, and thereby train more expressive synthesis algorithms. Our experiments and user study show the state-of-the-art quality of our speech-synthesized full 3D character animations.
Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe
2021-09-10

Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal and pulmonary fibrosis, atherosclerosis, and various forms of cancer. Potent and selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases such as the tyrosine protein kinase receptor TIE or tropomyosin receptor kinases, which are related to angiogenesis and neuronal toxicity. In this study, we optimized our recently published p38 mitogen-activated protein kinase inhibitor <b>7</b> toward a potent and cell-active dual DDR/p38 chemical probe and developed a structurally related negative control. The structure-guided design approach used provided insights into the P-loop folding process of p38 and how targeting of non-conserved amino acids modulates inhibitor selectivity. The developed and comprehensively characterized DDR/p38 probe, <b>30</b> (SR-302), is a valuable tool for studying the role of DDR kinase in normal physiology and in disease development.
A flow-based latent state generative model of neural population responses to natural images
2021-09-10

Abstract We present a joint deep neural system identification model for two major sources of neural variability: stimulus-driven and stimulus-conditioned fluctuations. To this end, we combine (1) state-of-the-art deep networks for stimulus-driven activity and (2) a flexible, normalizing flow-based generative model to capture the stimulus-conditioned variability including noise correlations. This allows us to train the model end-to-end without the need for sophisticated probabilistic approximations associated with many latent state models for stimulus-conditioned fluctuations. We train the model on the responses of thousands of neurons from multiple areas of the mouse visual cortex to natural images. We show that our model outperforms previous state-of-the-art models in predicting the distribution of neural population responses to novel stimuli, including shared stimulus-conditioned variability. Furthermore, it successfully learns known latent factors of the population responses that are related to behavioral variables such as pupil dilation, and other factors that vary systematically with brain area or retinotopic location. Overall, our model accurately accounts for two critical sources of neural variability while avoiding several complexities associated with many existing latent state models. It thus provides a useful tool for uncovering the interplay between different factors that contribute to variability in neural activity.
Inhibition of photoferrotrophy by nitric oxide in ferruginous environments
2021-09-10

Anoxygenic phototrophic Fe(II)-oxidizers (photoferrotrophs) are thought to have thrived in Earth’s ancient ferruginous oceans and played a primary role in the precipitation of Archean and Paleoproterozoic (3.8-1.85 Ga) banded iron formations (BIF). The end of BIF deposition by photoferrotrophs has often been interpreted as being the result a deepening of water column oxygenation below the photic zone concomitant with the proliferation of cyanobacteria. We suggest here that a potentially overlooked aspect influencing BIF precipitation by photoferrotrophs is competition with another anaerobic Fe(II)-oxidizing metabolism. It is speculated that microorganisms capable of coupling Fe(II) oxidation to the reduction of nitrate were also present early in Earth history when BIF were being deposited, but the extent to which they could compete with photoferrotrophs when favourable geochemical conditions overlapped is unknown. Utilizing microbial incubations and numerical modelling, we show that nitrate-reducing Fe(II)-oxidizers metabolically outcompete photoferrotrophs for dissolved Fe(II). Moreover, the nitrate-reducing Fe(II)-oxidizers inhibit photoferrotrophy via the production of toxic nitric oxide (NO). Four different photoferrotrophs, representing both green sulfur and purple non-sulfur bacteria, are susceptible to this toxic effect despite having genomic capabilities for NO detoxification. Indeed, despite NO detoxification mechanisms being ubiquitous in some groups of phototrophs at the genomic level (e.g. Chlorobi and Cyanobacteria) it is likely they would still be influenced by NO stress. We suggest that the production of NO during nitrate-reducing Fe(II) oxidation in ferruginous environments represents an as yet unreported control on the activity of photoferrotrophs in the ancient oceans and thus the mechanisms driving precipitation of BIF.
Impact of Alkanediols on Stratum Corneum Lipids and Triamcinolone Acetonide Skin Penetration
2021-09-11

Alkanediols are widely used as multifunctional ingredients in dermal formulations. In addition to their preservative effect, considering their possible impact on drug penetration is also essential for their use. In the present study, the influence of 2-methyl-2,4-pentanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol on the skin penetration of triamcinolone acetonide from four different semisolid formulations was investigated. Furthermore, confocal Raman spectroscopy measurements were performed to examine the influence of the alkanediols on stratum corneum lipid content and order. Alkanediols were found to increase the penetration of triamcinolone acetonide. However, the extent depends strongly on the formulation used. In certain formulations, 1,2-pentanediol showed the highest effect, while in others the penetration-enhancing effect increased with the alkyl chain length of the alkanediol used. None of the tested alkanediols extracted lipids from the stratum corneum nor reduced its thickness. Notwithstanding the above, the longer-chained alkanediols cause the lipids to be converted to a more disordered state, which favors drug penetration. This behavior could not be detected for the shorter-chained alkanediols. Therefore, their penetration-enhancing effect is supposed to be related to an interaction with the hydrophilic regions of the stratum corneum.
A rich and bountiful harvest: Key discoveries in plant cell biology
2021-09-11

Abstract The field of plant cell biology has a rich history of discovery, going back to Robert Hooke’s discovery of cells themselves. The development of microscopes and preparation techniques has allowed for the visualization of subcellular structures, and the use of protein biochemistry, genetics, and molecular biology has enabled the identification of proteins and mechanisms that regulate key cellular processes. In this review, seven senior plant cell biologists reflect on the development of this research field in the past decades, including the foundational contributions that their teams have made to our rich, current insights into cell biology. Topics covered include signaling and cell morphogenesis, membrane trafficking, cytokinesis, cytoskeletal regulation, and cell wall biology. In addition, these scientists illustrate the pathways to discovery in this exciting research field.
The Alkylaluminate/Gallate Trap: Metalation of Benzene by Heterobimetallic Yttrocene Complexes [Cp*2Y(MMe3R)] (M = Al, Ga)
2021-09-11

Yttrocene derivatives [Cp*<sub>2</sub>Y(MMe<sub>4</sub>)] (Cp* = C<sub>5</sub>Me<sub>5</sub>; M = Al, Ga) and Cp*<sub>2</sub>Y[Me<sub>3</sub>Al{B(NDippCH)<sub>2</sub>}] (Dipp = C<sub>6</sub>H<sub>3</sub><i>i</i>Pr<sub>2</sub>-2,6) deprotonate benzene at elevated temperatures via the release of methane. The formation of [Cp*<sub>2</sub>Y(Me<sub>2</sub>MPh<sub>2</sub>)] (M = Al, Ga), Cp*<sub>2</sub>Y(MPh<sub>4</sub>) (M = Al, Ga), Cp*<sub>2</sub>Y[Me<sub>2</sub>AlPh{B(NDippCH)<sub>2</sub>}], and Cp*<sub>2</sub>Y[AlPh<sub>3</sub>{B(NDippCH)<sub>2</sub>}] can be controlled via the temperature applied. The activation temperature and formation of the coordinatively unsaturated "reactive" [Cp*<sub>2</sub>YMe] strongly depend on the coordination strength of the displaceable Lewis acids [AlMe<sub>3</sub>]<sub>2</sub>, GaMe<sub>3</sub>, and [Me<sub>2</sub>Al{B(NDippCH)<sub>2</sub>}]<sub>2</sub>. Hence, [Cp*<sub>2</sub>Y(AlMe<sub>4</sub>)] requires temperatures above 100 °C to metalate benzene, while Cp*<sub>2</sub>Y[AlMe<sub>3</sub>{B(NDippCH)<sub>2</sub>}] undergoes C-H-bond activation even at ambient temperatures. A kinetic deuterium isotope effect was observed for the reactions in C<sub>6</sub>D<sub>6</sub> solutions. Distinct differences in the stabilities of the bulky Group 13 anions ([Me<sub>2</sub>MPh<sub>2</sub>]<sup>-</sup>, [MPh<sub>4</sub>]<sup>-</sup>, [Me<sub>3</sub>Al{B(NDippCH)<sub>2</sub>}]<sup>-</sup>, [Me<sub>2</sub>AlPh{B(NDippCH)<sub>2</sub>}]<sup>-</sup>, and [AlPh<sub>3</sub>{B(NDippCH)<sub>2</sub>}]<sup>-</sup>) are assessed by detailed studies of the coordination chemistry with tetrahydrofuran (THF) and by variable-temperature <sup>1</sup>H NMR spectroscopy. Thus, increased steric bulk or a reduced Lewis acidity of the Group 13 metal center promote temperature-sensitive dissociation of trivalent Group 13 alkyl entities. Consequently, compound Cp*<sub>2</sub>Y[AlPh<sub>3</sub>{B(NDippCH)<sub>2</sub>}] was found to engage in a dissociation equilibrium with [Cp*<sub>2</sub>YPh] and AlPh<sub>2</sub>{B(NDippCH)<sub>2</sub>} in a C<sub>6</sub>D<sub>6</sub> solution at ambient temperature. The reaction of Cp*<sub>2</sub>Y[AlPh<sub>3</sub>{B(NDippCH)<sub>2</sub>}] with THF results in the concomitant formation of monometallic Cp*<sub>2</sub>YPh(THF) and the solvent-separated ion pair [Cp*<sub>2</sub>Y(THF)<sub>2</sub>][AlPh<sub>3</sub>{B(NDippCH)<sub>2</sub>}].
Ge14Br8–xClx(PEt3)4: Insight into the Reaction Route to Metalloid Clusters of Germanium
2021-09-11

The isolation of the germanium mixed halide cluster Ge<sub>14</sub>Br<sub>8-<i>x</i></sub>Cl<sub><i>x</i></sub>(PEt<sub>3</sub>)<sub>4</sub> (<b>2</b>) by the reaction of a metastable Ge<sup>I</sup>Br solution (toluene/PEt<sub>3</sub>) with GeCl<sub>2</sub>·dioxane provides new insights into the complex formation mechanism of metalloid germanium clusters through the disproportionation reaction of Ge<sup>I</sup>X (X = Cl and Br). It is shown that the Ge<sup>II</sup> halide is involved in at least two steps in the build-up reaction of <b>2</b>. The molecular structure of <b>2</b> is presented together with a plausible reaction mechanism leading to the binary cluster Ge<sub>14</sub>Br<sub>8</sub>(PEt<sub>3</sub>)<sub>4</sub> and future aspects of these findings.
Endoscopically assisted implant removal of a symphyseal pelvic plate - A case report
2021-09-11

While we were able to show that the endoscopically assisted implantation as well as the removal of a plate osteosynthesis on the anterior pelvic ring is possible, there is still further research necessary, especially regarding the development of specific endoscopic instruments. This should enable operating times similar to the standard open procedures.
Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration
2021-09-11

Abstract Inherited retinal diseases (IRDs) are a group of neurodegenerative disorders that lead to photoreceptor cell death and eventually blindness. IRDs are characterised by a high genetic heterogeneity, making it imperative to design mutation-independent therapies. Mutations in a number of IRD disease genes have been associated with a rise of cyclic 3’,5’-guanosine monophosphate (cGMP) levels in photoreceptors. Accordingly, the cGMP-dependent protein kinase (PKG) has emerged as a new potential target for the mutation-independent treatment of IRDs. However, the substrates of PKG and the downstream degenerative pathways triggered by its activity have yet to be determined. Here, we performed kinome activity profiling of different murine organotypic retinal explant cultures (diseased rd1 and wild-type controls) using multiplex peptide microarrays to identify proteins whose phosphorylation was significantly altered by PKG activity. In addition, we tested the downstream effect of a known PKG inhibitor CN03 in these organotypic retina cultures. Among the PKG substrates were potassium channels belonging to the K v 1 family (KCNA3, KCNA6), Cyclic AMP-responsive element-binding protein 1 (CREB1), DNA topoisomerase 2-α (TOP2A), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (F263), and the glutamate ionotropic receptor kainate 2 (GRIK2). The retinal expression of these PKG targets was further confirmed by immunofluorescence and could be assigned to various neuronal cell types, including photoreceptors, horizontal cells, and ganglion cells. Taken together, this study confirmed the key role of PKG in photoreceptor cell death and identified new downstream targets of cGMP/PKG signalling that will improve the understanding of the degenerative mechanisms underlying IRDs.
Clonal evolution and specificity of the human T follicular helper cell response toPlasmodium falciparumcircumsporozoite protein
2021-09-11

ABSTRACT T follicular helper (T FH ) cells play a crucial role in the development of long-lived, quality-improved B cell responses after infection and vaccination. However, little is known about their clonal evolution. Here we assessed the cell phenotype, clonal dynamics, and TCR specificity of human circulating T FH (cT FH ) cells at monoclonal level during successive malaria immunizations with radiation-attenuated Plasmodium falciparum ( Pf ) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cT FH response with high frequency of cells specific to the Pf circumsporozoite protein (PfCSP), the main surface protein of sporozoites and a validated vaccine target. Repeated immunizations were required to induce detectable PfCSP-reactive cT FH cell responses to a small number of epitopes. HLA-restrictions and differences in TCR generation probability explain the high targeting frequency of the polymorphic Th2R/T* region over the conserved T1 epitope. The vast majority of anti-Th2R/T* TCRs failed to tolerate natural polymorphisms in their target peptide sequence suggesting that parasite diversity limits natural boosting of the cT FH cell response in endemic areas and protection from non-vaccine strains. Among convergent anti-Th2R/T* TCRs with high sequence similarity, subtle differences in CDR3 composition discriminated cross-reactive from non-cross-reactive cT FH cells. Thus, our study provides deep molecular and cellular insights into the kinetics, fine specificity and HLA-restrictions of the anti-cT FH cell response that are of direct relevance for the design of PfCSP-based malaria vaccines by guiding the selection of PfCSP peptides that induce optimal B cell help.
Social mobility and gonorrhoea in Germany during 2020
2021-09-11

Objectives The incidence of STIs is likely to be related to levels of social activity and mobility. Novel datasets detailing levels of social activity were made widely available during the COVID-19 pandemic. These allow the relationship between activity and STI incidence to be examined. Methods The correlation between social activities and the reported number of gonorrhoea cases between March and December 2020 in Germany was studied. Regression through Autoregressive Integrated Moving Average (ARIMA) time series modelling identified those activities associated with case numbers. Results ARIMA regression identified a significant association with ‘transit’ activity within the Apple data and ‘parks’ within Google. Conclusions This study illustrates the potential newly available measures of social activity provided for STI research. Reductions in STI incidence are likely to have occurred due to COVID-19 social restrictions. Although other studies report reductions in infectious diseases during this period, few examine the potential social factors mediating this. The results illustrate the continual need for sexual health services throughout the pandemic.
Environmental stress determines the colonization and impact of an endophytic fungus on invasive knotweed
2021-09-11

Abstract There is increasing evidence that microbes play a key role in some plant invasions. A diverse and widespread but little understood group of plant-associated microbes are the fungal root endophytes of the order Sebacinales. They are associated with exotic populations of invasive knotweed ( Reynoutria ssp.) in Europe, but their effects on the invaders are unknown. We used the recently isolated Sebacinales root endophyte S erendipita herbamans to experimentally inoculate invasive knotweed and study root colonisation and effects on knotweed growth under different environmental conditions. We verified the inoculation success and fungal colonisation through immunofluorescence microscopy and qPCR. We found that S. herbamans strongly colonized invasive knotweed in low-nutrient and shade environments, but much less under drought or benign conditions. At low nutrients, the endophyte had a positive effect on plant growth, whereas the opposite was true under shaded conditions. Synthesis. Our study demonstrates that the root endophyte S. herbamans has the potential to colonize invasive knotweed fine roots and impact its growth, and it could thus also play a role in natural populations. Our results also show that effects of fungal endophytes on plants can be strongly environment-dependent, and may only be visible under stressful environmental conditions.
Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced‐intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT
2021-09-12

Summary Allogeneic haematopoietic‐cell transplantation (allo‐HCT) is a potentially curative therapy for high‐risk myelodysplastic syndrome (MDS). Reduced‐intensity conditioning (RIC) is usually associated with lower non‐relapse mortality (NRM), higher relapse rate and similar overall‐survival (OS) as myeloablative‐conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced‐toxicity regimen with intense anti‐leukaemia activity and a favourable toxicity profile. We investigated post‐transplant outcomes in 1722 MDS patients following allo‐HCT with FT ( n = 367), RIC ( n = 687) or MAC ( n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively ( P &lt; 0·001) but other disease characteristics were similar. The median follow‐up was 64 months (1–171). Five‐year relapse rates were 25% (21–30), 38% (34–42) and 25% (22–29), after FT, RIC and MAC, respectively, ( P &lt; 0·001). NRM was 30% (25–35), 27% (23–30) and 34% (31–38, P = 0·008), respectively. Five‐year OS was 50% (44–55), 43% (38–47), and 43% (39–47), respectively ( P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P &lt; 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo‐HCT in MDS.