julilili42/papers huggingface dataset:
Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain
2023-03-23

Inherited retinal degeneration (IRD) represents a diverse group of gene mutation-induced blinding diseases. In IRD, the loss of photoreceptors is often connected to excessive activation of histone-deacetylase (HDAC), poly-ADP-ribose-polymerase (PARP), and calpain-type proteases (calpain). Moreover, the inhibition of either HDACs, PARPs, or calpains has previously shown promise in preventing photoreceptor cell death, although the relationship between these enzyme groups remains unclear. To explore this further, organotypic retinal explant cultures derived from wild-type mice and rd1 mice as a model for IRD were treated with different combinations of inhibitors specific for HDAC, PARP, and calpain. The outcomes were assessed using in situ activity assays for HDAC, PARP, and calpain, immunostaining for activated calpain-2, and the TUNEL assay for cell death detection. We confirmed that inhibition of either HDAC, PARP, or calpain reduced rd1 mouse photoreceptor degeneration, with the HDAC inhibitor Vorinostat (SAHA) being most effective. Calpain activity was reduced by inhibition of both HDAC and PARP whereas PARP activity was only reduced by HDAC inhibition. Unexpectedly, combined treatment with either PARP and calpain inhibitors or HDAC and calpain inhibitors did not produce synergistic rescue of photoreceptors. Together, these results indicate that in rd1 photoreceptors, HDAC, PARP, and calpain are part of the same degenerative pathway and are activated in a sequence that begins with HDAC and ends with calpain.
The Lab as a Classroom: Advancing Faculty Research Through Undergraduate Experiential Education
2023-03-23

ABSTRACT Both undergraduate students and faculty members face a challenging job market that requires innovative approaches to skill development and research products. Moreover, entrenched approaches to research and education reinforce traditional hierarchies, exclusionary norms, and exploitative practices. This article describes a lab-based pedagogical framework designed to support faculty research goals and student learning and, simultaneously, to attenuate patterns of historical exclusion. This approach leverages evidence-based best practices from experiential education, team-based workflows, an understanding of servant leadership, and “whole-person”–style mentorship models. We find that these tools advance faculty research goals (in terms of both quality and productivity), support student learning in ways beyond traditional undergraduate coursework, and disrupt patterns of historical exclusion. We provide qualitative evidence to support our model and discuss the hurdles and challenges still to be overcome.
Impact of the returning radiation in current tests of the Kerr black hole hypothesis using X-ray reflection spectroscopy
2023-03-23

The past 10 years have seen remarkable progress in our capability of analyzing reflection features in the X-ray spectra of accreting black holes. Today X-ray reflection spectroscopy is a mature technique and a powerful tool for studying the accretion process around black holes, measuring black hole spins, and testing Einstein's theory of General Relativity in the strong field regime. However, current reflection models still rely on a number of simplifications and caution is necessary when we derive very precise measurements. In this paper, we study the impact of the returning radiation on our capability of measuring the properties of black holes using X-ray reflection spectroscopy, and in particular on our capability of testing the Kerr black hole hypothesis. While the returning radiation alters the reflection spectrum of the disk, from the analysis of our simulations we find that models without returning radiation can normally recover well the correct black hole spin parameters and can test the Kerr metric. Our study thus confirms that current tests of the Kerr hypothesis using X-ray reflection spectroscopy can be robust.
A modified pull-through approach with a pedicled bone flap for oral and oropharyngeal cancer resection - a cadaveric feasibility study
2023-03-23

Abstract Purpose Compromised swallowing and speaking as well as local complications are the major disadvantages of established approaches to the posterior tongue and oropharynx. The mandibular split involves an esthetically unpleasant bipartition of the lower lip and is prone to bony non-union or sequestration. The traditional pull-through technique on the other hand lacks the safe reattachment of the lingually released soft tissues. Methods The feasibility of a new modified pull-through approach was tested on three anatomical specimens. CAD/CAM cutting guides were used to design a retentive bone flap for the proper refixation of the genioglossus and geniohyoid muscles after the procedure. Results Precise repositioning and dynamic compression of bony segments was reproducible and no injury to adjacent structures occurred. In all cases, a median lingual foramen was found and in two cases vessels entering it could be dissected. Conclusion The method presented is safe and easy to perform. Individual cutting guides improve the safety and accuracy of the procedure, potentially eliminating the need for osteosynthesis. We provide the anatomical and radiologic basis for clinical evaluation of this pedicled bone flap procedure.
Proteome‐wide lysine acetylation profiling to investigate the involvement of histone deacetylase HDA5 in the salt stress response of Arabidopsis leaves
2023-03-24

SUMMARY Post‐translational modifications (PTMs) of proteins play important roles in the acclimation of plants to environmental stress. Lysine acetylation is a dynamic and reversible PTM, which can be removed by histone deacetylases. Here we investigated the role of lysine acetylation in the response of Arabidopsis leaves to 1 week of salt stress. A quantitative mass spectrometry analysis revealed an increase in lysine acetylation of several proteins from cytosol and plastids, which was accompanied by altered histone deacetylase activities in the salt‐treated leaves. While activities of HDA14 and HDA15 were decreased upon salt stress, HDA5 showed a mild and HDA19 a strong increase in activity. Since HDA5 is a cytosolic‐nuclear enzyme from the class II histone deacetylase family with yet unknown protein substrates, we performed a lysine acetylome analysis on hda5 mutants and characterized its substrate proteins. Next to histone H2B, the salt stress‐responsive transcription factor GT2L and the dehydration‐related protein ERD7 were identified as HDA5 substrates. In addition, in protein–protein interaction studies, HDA18 was discovered, among other interacting proteins, to work in a complex together with HDA5. Altogether, this study revealed the substrate proteins of HDA5 and identified new lysine acetylation sites which are hyperacetylated upon salt stress. The identification of specific histone deacetylase substrate proteins, apart from histones, will be important to unravel the acclimation response of Arabidopsis to salt stress and their role in plant physiology.
Foundation model of neural activity predicts response to new stimulus types and anatomy
2023-03-24

The complexity of neural circuits makes it challenging to decipher the brain’s algorithms of intelligence. Recent break-throughs in deep learning have produced models that accurately simulate brain activity, enhancing our understanding of the brain’s computational objectives and neural coding. However, these models struggle to generalize beyond their training distribution, limiting their utility. The emergence of foundation models, trained on vast datasets, has introduced a new AI paradigm with remarkable generalization capabilities. We collected large amounts of neural activity from visual cortices of multiple mice and trained a foundation model to accurately predict neuronal responses to arbitrary natural videos. This model generalized to new mice with minimal training and successfully predicted responses across various new stimulus domains, such as coherent motion and noise patterns. It could also be adapted to new tasks beyond neural prediction, accurately predicting anatomical cell types, dendritic features, and neuronal connectivity within the MICrONS functional connectomics dataset. Our work is a crucial step toward building foundation brain models. As neuroscience accumulates larger, multi-modal datasets, foundation models will uncover statistical regularities, enabling rapid adaptation to new tasks and accelerating research.
Private Vehicles Greenhouse Gas Emission Estimation at Street Level for Berlin Based on Open Data
2023-03-24

As one of the major greenhouse gas (GHG) emitters that has not seen significant emission reductions in the previous decades, the transportation sector requires special attention from policymakers. Policy decisions, thereby need to be supported by traffic emission assessments. Estimations of traffic emissions often rely on huge amounts of actual traffic data whose availability is limited, hampering the transferability of the estimation approaches in time and space. Here, we propose a high-resolution estimation of traffic emissions, which is based entirely on open data, such as the road network and points of interest derived from OpenStreetMap (OSM). We estimated the annual average daily GHG emissions from individual motor traffic for the OSM road network in Berlin by combining the estimated Annual Average Daily Traffic Volume (AADTV) with respective emission factors. The AADTV was calculated by simulating car trips with the open routing engine Openrouteservice, weighted by activity functions based on statistics of the German Mobility Panel. Our estimated total annual GHG emissions were 7.3 million t CO2 equivalent. The highest emissions were estimated for the motorways and major roads connecting the city center with the outskirts. The application of the approach to Berlin showed that the method could reflect the traffic pattern. As the input data is freely available, the approach can be applied to other study areas within Germany with little additional effort.
Epigenetic cues regulating airway development in human lung organoids: Polycomb repressive complex 2 and altered chromatin accessibility determine cell fate
2023-03-24

Abstract Today, human organoids are becoming an integrated part of genomics and epigenomics, as they provide a platform that can be used for the definite study of molecular and cellular mechanisms occurring at different stages of development, particularly organogenesis, within the human body. Airway development is a complex process heavily influenced by epigenetic regulatory mechanisms in response to environmental changes, and as such, human lung organoids are an indispensable asset for further exploration of these mechanisms as a mode of transition from human in vitro to human ex vivo studies. Cultured primarily in compounds mimicking the extracellular matrix, such as Matrigel, these lung organoids have helped us to come to a better understanding of the role of polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2) in lung epithelial cell differentiation and airway development, which was first reported in the FASEB journal in 2019. The following is an extended account of how the histone methylation‐regulating PRC2 comes to play in the molding of the human bronchial tree, along with further epigenetic insights based on more recently developed human lung organoids.
Explaining Regularities or Individual Outcomes: Chance and the Limits of Social Science
2023-03-24

Can we explain individual outcomes by referring to patterns observed in populations? Social scientists generally assume that we can, at least to a certain degree, and they study populations partly with that goal in mind. However, while patterns can be observed on the population level, which suggest that, on average, certain segments of the population are more likely to experience some outcome, it is impossible, on the individual level, to predict who will actually experience the outcome, even if the individual’s relevant characteristics are known. Thus, an interesting tension emerges: on the one hand, individual action and experience produces population-level patterns, while on the other hand, individual experience appears to be ‘inherently underdetermined’ and partly or largely due to luck or chance. Accordingly, this article considers the relationship between regularities and individual outcomes and to what extent it is desirable to construct models which can explain all the variance in outcomes, and the roles of true chance and what one might call ‘as-if’ chance in this. An empirical demonstration based on ALLBUS data explores these issues further. It uses the example of the graduate premium to discuss that, while there is a pattern where, on average, graduates earn more than non-graduates, there is a certain degree of individual-level deviation from this pattern (even after taking account of other relevant factors) which is partly due to chance. Patterns identified in data can provide the upper and lower bounds within which chance plays its part. The article closes with a discussion of implications for research and policy, and for the understanding of research findings by the general public.
Supporting material for PyESDv1.0.1 An open-source Python framework for empirical-statistical downscaling of climate information
2023-03-24

&lt;p&gt;The nature and severity of climate change impacts varies significantly from region to region. Consequently, high-resolution climate information is needed for meaningful impact assessments and the design of mitigation strategies. This demand has led to an increase in the coupling of Empirical Statistical Downscaling (ESD) models to General Circulation Model (GCM) simulations of future climate. Here, we present a new open-source Python package (&lt;em&gt;pyESD;&nbsp;&lt;/em&gt;github.com/Dan-Boat/PyESD) that implements several Perfect Prognosis ESD (PP-ESD) methods and the whole downscaling cycle. The latter includes routines for data preparation, predictor selection and construction, model selection and training, evaluation, utility tools for relevant statistical tests, visualization, and more. The package includes a collection of well-established Machine Learning algorithms and allows the user to choose a variety of estimators, cross-validation schemes, objective function measures, hyperparameter optimization, etc., in relatively few lines of code. The package is highly modular and flexible and allows quick and reproducible downscaling of any climate information, such as precipitation, temperature, wind speed, or even glacial retreat. The dataset presented here serves as supporting material for the package description and evaluation manuscript&lt;/p&gt;
Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily
2023-03-24

ABSTRACT Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicity in vivo , which complicates the use of MRIA9 as a tool compound. Here, we present a structure-based approach involving the back-pocket and gatekeeper residues, for narrowing the selectivity of pyrido[2,3-d]pyrimidin-7(8 H )-one-based inhibitors towards SIK kinases, eliminating PAK activity. Optimization was guided by high-resolution crystal structure analysis and computational methods, resulting in a pan-SIK inhibitor, MR22, which no longer exhibited activity on STE group kinases and displayed excellent selectivity in a representative kinase panel. MR22-dependent SIK inhibition led to centrosome dissociation and subsequent cell-cycle arrest in ovarian cancer cells, as observed with MRIA9, conclusively linking these phenotypic effects to SIK inhibition. Taken together, MR22 represents a valuable tool compound for studying SIK kinase function in cells.
Supporting material for PyESDv1.0.1 An open-source Python framework for empirical-statistical downscaling of climate information
2023-03-24

The nature and severity of climate change impacts varies significantly from region to region. Consequently, high-resolution climate information is needed for meaningful impact assessments and the design of mitigation strategies. This demand has led to an increase in the coupling of Empirical Statistical Downscaling (ESD) models to General Circulation Model (GCM) simulations of future climate. Here, we present a new open-source Python package (<em>pyESD; </em>github.com/Dan-Boat/PyESD) that implements several Perfect Prognosis ESD (PP-ESD) methods and the whole downscaling cycle. The latter includes routines for data preparation, predictor selection and construction, model selection and training, evaluation, utility tools for relevant statistical tests, visualization, and more. The package includes a collection of well-established Machine Learning algorithms and allows the user to choose a variety of estimators, cross-validation schemes, objective function measures, hyperparameter optimization, etc., in relatively few lines of code. The package is highly modular and flexible and allows quick and reproducible downscaling of any climate information, such as precipitation, temperature, wind speed, or even glacial retreat. The dataset presented here serves as supporting material for the package description and evaluation manuscript
Untangling TMS‐EEG responses caused by TMS versus sensory input using optimized sham control and GABAergic challenge
2023-03-25

Abstract The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) elegantly probes the excitability and connectivity of the human brain. However, TMS‐EEG signals inevitably also contain sensory‐evoked responses caused by TMS‐associated auditory and somatosensory inputs, constituting a substantial confounding factor. Here we applied our recently established optimized SHAM protocol (Gordon et al., Neuroimage 2021:118708) to disentangle TMS‐EEG responses caused by TMS vs . sensory input. One unresolved question is whether these responses superimpose without relevant interaction, a requirement for their disaggregation by the optimized SHAM approach. We applied in 20 healthy subjects a pharmacological intervention using a single oral dose of 20 mg of diazepam, a positive modulator of GABAA receptors. Diazepam decreased the amplitudes of the P60 and P150 components specifically in the ACTIVE TMS and/or the ACTIVE TMS minus SHAM conditions but not in the SHAM condition, pointing to a response caused by TMS. In contrast, diazepam suppressed the amplitude of the N100 component indiscriminately in the ACTIVE TMS and SHAM conditions but not in the ACTIVE TMS minus SHAM condition, pointing to a response caused by sensory input. Moreover, diazepam suppressed the beta‐band response observed in the motor cortex specifically after ACTIVE TMS and ACTIVE TMS minus SHAM. These findings demonstrate a lack of interaction of TMS‐EEG responses caused by TMS vs . sensory input and validate optimized SHAM‐controlled TMS‐EEG as an appropriate approach to untangle these TMS‐EEG responses. This knowledge will enable the proficient use of TMS‐EEG to probe the physiology of the human cortex. image Key points Optimized SHAM disentangles TMS‐EEG responses caused by TMS vs . sensory input. Diazepam differentially modulates TMS‐EEG responses caused by TMS vs . sensory input. Diazepam modulation of P60 and P150 indicate TMS‐EEG responses caused by TMS. Diazepam modulation of N100 indicate a TMS‐EEG response caused by sensory input.
Carrier Localization on the Nanometer‐Scale limits Transport in Metal Oxide Photoabsorbers
2023-03-25

Abstract Metal oxides are considered as stable and low‐cost photoelectrode candidates for hydrogen production by photoelectrochemical solar water splitting. However, their power conversion efficiencies usually suffer from poor transport of photogenerated charge carriers, which has been attributed previously to a variety of effects occurring on different time and length scales. In search for common understanding and for a better photo‐conducting metal oxide photoabsorber, CuFeO 2 , α‐SnWO 4 , BaSnO 3 , FeVO 4 , CuBi 2 O 4 , α‐Fe 2 O 3 , and BiVO 4 are compared. Their kinetics of thermalization, trapping, localization, and recombination are monitored continuously 100 fs–100 μs and mobilities are determined for different probing lengths by combined time‐resolved terahertz and microwave spectroscopy. As common issue, we find small mobilities &lt; 3 cm 2 V ‐1 s ‐1 . Partial carrier localization further slows carrier diffusion beyond localization lengths of 1–6 nm and explains the extraordinarily long conductivity tails, which should not be taken as a sign of long diffusion lengths. For CuFeO 2 , the localization is attributed to electrostatic barriers that enclose the crystallographic domains. The most promising novel material is BaSnO 3 , which exhibits the highest mobility after reducing carrier localization by annealing in H 2 . Such overcoming of carrier localization should be an objective of future efforts to enhance charge transport in metal oxides.
Synthetic Curcumin Analogues Present Antiflavivirus Activity In Vitro with Potential Multiflavivirus Activity from a Thiazolylhydrazone Moiety
2023-03-25

Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections.