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Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner
Get PDFBackground: Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process.
Results: We establish a new in vitro culture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environment in vivo. We demonstrate that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we show that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrate that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion.
Conclusions: Our data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process
Intraocular Lens Power Calculation—Comparing Big Data Approaches to Established Formulas
Get PDFPurpose
To evaluate the predictive performance of traditional intraocular lens (IOL) power calculation formulas (e.g., SRK/T, Haigis, Hoffer Q, and Holladay I) compared to advanced regression models, including classical linear models, regression splines, and random forest regression, in predicting postoperative refraction following cataract surgery.
Design
Retrospective, comparative analysis of IOL power calculations.
Subjects
The study included 886 eyes from 631 patients who underwent cataract surgery with monofocal aspherical IOL implantation.
Methods
Biometric measurements were obtained using optical biometry (IOLMaster 700), and postoperative refraction was assessed at least 4 weeks after surgery. Formula constants for 5 IOL formulas (SRK/T, Haigis, Hoffer Q, Holladay I and Castrop V1) were optimized using root mean squared error (RMSE). Regression models (classical linear model, regression splines, and random forest regression) were trained on 4 datasets categorized by axial length (AL); normal, short, long, and random. Model performance was assessed using mean absolute error (MAE), RMSE, and prediction error variance, for both in-sample and out-of-sample predictions.
Main Outcome Measures
The primary parameters measured were MAE, RMSE, and prediction error variance.
Results
Regression models outperformed traditional IOL formulas in in-sample prediction error. Overall, linear regression models performed similarly to traditional formulas with respect to out-of-sample prediction error. The lowest out-of-sample prediction error (MAE = 0.279, RMSE = 0.359) was achieved with a model where effects of some covariates (R2, AL, CCT) were modelled as nonlinear via regression splines. This model outperformed all traditional formulas, and the Castrop formula, which had the lowest errors among the formulas (MAE = 0.284, RMSE = 0.359). Random forest regression showed strong in-sample performance but poor out-of-sample generalizability due to overfitting.
Conclusions
Regression models which allow for nonlinear effects, e.g. based on regression splines, provide a promising alternative to traditional IOL formulas for predicting postoperative refraction. Linear regression and random forest regression models can reduce in-sample error, however, their clinical utility is currently limited by out-of-sample performance. Future work should focus on improving generalizability and integrating machine learning models into clinical practice to enhance refractive outcomes, especially for eyes with atypical anatomy
When Do Liberal Governments Restrict Civil Society?
Get PDFLiberal democracies increasingly restrict civil society organizations (CSOs), a trend frequently linked to illiberal governments. But when do ideologically liberal governments resort to such restrictions? Linking research on state traditions, party ideology and crisis governance, we theorize factors enhancing liberal governments' propensity to adopt normatively contentious CSO restrictions. Distinguishing formal-legal restrictions on CSO voice from those on CSO existence, we show that nearly 90 such restrictions were adopted by 17 cabinets in France and the United Kingdom over the last 2 decades. In line with theoretical expectations, restrictions on CSO existence are more prominent in statist France, while governments in the United Kingdom tend to restrict CSO voice. More right-wing governments adopt more CSO restrictions, while restrictions go up with government crisis pressure. Overall, understanding how liberal governments use CSO restrictions requires considering contextual opportunity structures and ideological dispositions in conjunction
Novel approaches to CAR T cell target identification in acute myeloid leukemia
Get PDFIdentifying safe and effective CAR T cell targets in acute myeloid leukemia (AML) is challenging due to the disease’s complexity and overlap with normal hematopoiesis. This review highlights advances in target discovery for AML, emphasizing innovative approaches. Structural surfaceomics identifies tumor-specific protein conformations, while AI-driven single-cell RNA sequencing integrates multi-source data to pinpoint optimal targets. Refined cell surface capture technology maps the AML surfaceome without relying on predefined antibodies. These strategies enhance CAR T cell specificity and minimize off-tumor effects, offering promising pathways for safer and more effective AML treatments and broader cancer therapies
Recycling constructional patterns: The role of chunks in early bilingual acquisition
No full textAims and Objectives:
Over the last decades, usage-based research into child language acquisition has shown that multi-word units play a key role in child language acquisition. This paper sets out to explore the role of multi-word units in the bilingual speech of two German-English bilingual children, focusing on their code-mixing and starting from the hypothesis that code-mixed utterances can be accounted for with the help of constructional patterns that are in turn abstracted away from recurrent multi-word units.
Approach:
We used the Chunk-Based Learner (CBL), a computational model developed by Stewart McCauley and Morten Christiansen.
Data and Analysis:
We applied the CBL to longitudinal data from two children growing up bilingually with the same language pair (German-English) but notably different input situations, to detect recurrent multi-word units in the data.
Conclusions:
The study shows that both monolingual and code-mixed utterances are built from the same constructional patterns, highlighting the crucial role of chunks in language acquisition. Although code-mixed utterances appear highly creative, they largely rely on fixed, formulaic patterns similar to those found in monolingual speech. This finding supports the usage-based approach, suggesting that chunk-based learning is fundamental across different language acquisition contexts.
Originality:
Using a strictly bottom-up approach allows us to identify recurrent chunks that are used as “building blocks” of early child language, including, importantly, code-mixed utterances.
Significance:
Our study adds to previous research emphasizing the role of multi-word units in early bilingual acquisition and contributes to ongoing efforts to pinpoint the way in which constructional patterns emerge from multi-word units in more detail
Abwehr, Anerkennung, Aneignung. Die nationalsozialistischen Medizinverbrechen als historisch-ethische Herausforderung
Get PDFPIMAEX: Multi-Agent Exploration Through Peer Incentivization
Get PDFWhile exploration in single-agent reinforcement learning has been studied extensively in recent years, consid-erably less work has focused on its counterpart in multi-agent reinforcement learning. To address this issue, this work proposes a peer-incentivized reward function inspired by previous research on intrinsic curiosity and influence-based rewards. The PIMAEX reward, short for Peer-Incentivized Multi-Agent Exploration, aims to improve exploration in the multi-agent setting by encouraging agents to exert influence over each other to increase the likelihood of encountering novel states. We evaluate the PIMAEX reward in conjunction with PIMAEX-Communication, a multi-agent training algorithm that employs a communication channel for agents to influence one another. The evaluation is conducted in the Consume/Explore environment, a partially observable environment with deceptive rewards, specifically designed to challenge the exploration vs. exploitation dilemma and the credit-assignm ent problem. The results empirically demonstrate that agents using the PI-MAEX reward with PIMAEX-Communication outperform those that do not
Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease
Get PDFIntroduction: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
Methods: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
Results: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
Discussion: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible
Therapeutic sphingosine-1-phosphate receptor modulation by repurposing fingolimod (FTY720) leads to mitigated neuropathy and improved clinical outcome in a mouse model for Charcot-Marie-Tooth 1X disease
Get PDFPrevious studies have shown that both the innate and adaptive immune systems foster progression of neuropathy and clinical symptoms in a mouse model for Charcot-Marie-Tooth 1X disease. Here we demonstrate a possible therapeutic translation of these findings using the clinically approved sphingosine-1-phosphate receptor modulator fingolimod (FTY720) in connexin32-deficient mice mimicking Charcot-Marie-Tooth 1X disease.
Treatment with FTY720 prevented an increase of CD8+ and CD4+ T-lymphocyte numbers in both femoral quadriceps nerve as well as in ventral spinal roots. While macrophages of ventral spinal roots show a similar, albeit non-significant trend, macrophages from quadriceps nerve are not reduced upon treatment. On the histopathological level, axonopathic changes were reduced in ventral spinal roots, but not in quadriceps nerves upon treatment. Electrophysiological recordings displayed improved nerve conduction parameters upon FTY720 treatment, while clinically, FTY720 treatment ameliorated distinct parameters of motor performance and grip strength. We suggest that targeting the adaptive immune system might be a pharmacological treatment option for mitigating disease burden particularly in severe cases of Charcot-Marie-Tooth 1X
Structural investigations of benzoyl fluoride and the benzoacyl cation of low-melting compounds and reactive intermediates
Get PDFAcyl fluorides and acyl cations represent typical reactive intermediates in organic reactions, such as Friedel–Crafts acylation. However, the comparatively stable phenyl-substituted compounds have not been fully characterized yet, offering a promising backbone. Attempts to isolate the benzoacylium cation have only been carried out starting from the acyl chloride with weaker chloride-based Lewis acids. Therefore, only adducts of 1,4-stabilized acyl cations could be obtained. Due to the low melting point of benzoyl fluoride, together with its volitality and sensitivity toward hydrolysis, the structures of the acyl fluoride and its acylium cation have not been determined. Herein, we report the first crystal structure of benzoyl fluoride, C7H5FO or PhCOF (monoclinic P21/n, Z = 8) and the benzoacylium undecafluorodiarsenate, C7H5O+·As2F11− or [PhCO]+[As2F11]− (monoclinic P21/n, Z = 4). The compounds were characterized by low-temperature vibrational spectroscopy and single-crystal X-ray analysis, and are discussed together with quantum chemical calculations. In addition, their specific π-interactions were elucidated