julilili42/papers huggingface dataset:
Further delineation of the SCAF4-associated neurodevelopmental disorder
2024-12-12

Abstract While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4 -associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of SCAF4 variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.
About the accuracy of the relxill/relxill_nk models in view of the next generation of X-ray missions
2024-12-12

ABSTRACT X-ray reflection spectroscopy is a powerful tool to study the strong gravity region of black holes. The next generation of astrophysical X-ray missions promises to provide unprecedented high-quality data, which could permit us to get very precise measurements of the properties of the accretion flow and of the space–time geometry in the strong gravity region around these objects. In this work, we test the accuracy of the relativistic calculations of the reflection model relxill and of its extension to non-Kerr space–times relxill_nk in view of the next generation of X-ray missions. We simulate simultaneous observations with Athena/X-IFU and LAD of bright Galactic black holes with a precise and accurate ray-tracing code and we fit the simulated data with the latest versions of relline and relline_nk. While we always recover the correct input parameters, we find residuals in the fits when the emission from the inner part of the accretion disc is higher. Such residuals disappear if we increase the number of interpolation points on the disc in the integral of the transfer function. We also simulate full reflection spectra and find that the emission angle from the accretion disc should be treated properly in this case.
Insertion Behavior of Dialkylgermylene Ge(FluTMS)2 in Different E–X σ Bonds (E = Au, Si, Ge, Sn) and Its Relevance for Germanium Cluster Formation
2024-12-12

We present the insertion behavior of the alkyl-substituted germylene Ge(Flu<sup>TMS</sup>)<sub>2</sub> in different E-X σ bonds (E = Au, Si, Ge, Sn), first with the isolation of the germylgold complex (Flu<sup>TMS</sup>)<sub>2</sub>Ge(Cl)AuPPh<sub>3</sub>. Afterward, the oxidative addition of GeCl<sub>4</sub> to Ge(Flu<sup>TMS</sup>)<sub>2</sub> gives the digermane (Flu<sup>TMS</sup>)<sub>2</sub>Ge(Cl)GeCl<sub>3</sub>, followed by a reductive elimination of GeCl<sub>2</sub> and the formation of the oxidation product (Flu<sup>TMS</sup>)<sub>2</sub>GeCl<sub>2</sub>. A comparable behavior is observed, with the homologues ECl<sub>4</sub> (E = Si, Sn) stopping at different steps of the reaction. The formation of the germylgermylene (Flu<sup>TMS</sup>)<sub>2</sub>Ge(Cl)GeCl starting from Ge(Flu<sup>TMS</sup>)<sub>2</sub> and GeCl<sub>2</sub>·dioxane is also spectroscopically observable, followed by ligand rearrangements to the tetramer [Flu<sup>TMS</sup>GeCl]<sub>4</sub>. Adding a phosphine as the Lewis base has a direct influence on the stability and structure of (Flu<sup>TMS</sup>)<sub>2</sub>Ge(Cl)GeCl, leading to the formation of Flu<sup>TMS</sup>GeCl·PEt<sub>3</sub> as a stable product. Subsequent investigations of Ge(Flu<sup>TMS</sup>)<sub>2</sub> with a metastable Ge(I)Br solution show that at a ratio of 6:1 GeBr/Ge(Flu<sup>TMS</sup>)<sub>2</sub> the alkyl-substituted germylene no longer acts as a redox-active agent but as a cluster building block. This link and the involvement of a germylene in insertion reactions give an indication of how the construction or expansion of Ge cluster species can operate.
Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation
2024-12-12

Abstract Introduction While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington’s disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions. Methods Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier. Results One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03–0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed—in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions—HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration. Conclusions Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which—given the low repeat number—is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.
Statistical learning of foreign language words in younger and older adults
2024-12-12

Abstract Statistical learning, that is, our ability to track and learn from distributional information in the environment, plays a fundamental role in language acquisition, yet little research has investigated this process in older language learners. In the present study, we address this gap by comparing the cross-situational learning of foreign words in younger and older adults. We also tested whether learning was affected by previous experience with multiple languages. We found that both age groups successfully learned the novel words after a short exposure period, confirming that statistical learning ability is preserved in late adulthood. However, the two groups differed in their learning trajectories, with the younger group outperforming the older group during the later stages of learning. Previous language experience did not predict learning outcomes. Given that implicit language learning mechanisms are shown to be preserved over the lifespan, the present data provide crucial support for the assumptions underlying claims that language learning interventions in older age could be leveraged as a targeted intervention to help build or maintain resilience to age-related cognitive decline.
The cellular and extracellular proteomic signature of human dopaminergic neurons carrying the LRRK2 G2019S mutation
2024-12-12

Background Extracellular vesicles are easily accessible in various biofluids and allow the assessment of disease-related changes in the proteome. This has made them a promising target for biomarker studies, especially in the field of neurodegeneration where access to diseased tissue is very limited. Genetic variants in the LRRK2 gene have been linked to both familial and sporadic forms of Parkinson’s disease. With LRRK2 inhibitors entering clinical trials, there is an unmet need for biomarkers that reflect LRRK2-specific pathology and target engagement. Methods In this study, we used induced pluripotent stem cells derived from a patient with Parkinson’s disease carrying the LRRK2 G2019S mutation and an isogenic gene-corrected control to generate human dopaminergic neurons. We isolated extracellular vesicles and neuronal cell lysates and characterized their proteomic signature using data-independent acquisition proteomics. Then, we performed differential expression analysis to identify dysregulated proteins in the mutated line. We used Metascape and gene ontology enrichment analysis on the dysregulated proteomes to identify changes in associated functional networks. Results We identified 595 significantly differentially regulated proteins in extracellular vesicles and 3,205 in cell lysates. We visualized functionally relevant protein–protein interaction networks and identified key regulators within the dysregulated proteomes. Using gene ontology, we found a close association with biological processes relevant to neurodegeneration and Parkinson’s disease. Finally, we focused on proteins that were dysregulated in both the extracellular and cellular proteomes. We provide a list of ten biomarker candidates that are functionally relevant to neurodegeneration and linked to LRRK2-associated pathology, for example, the sonic hedgehog signaling molecule, a protein that has tightly been linked to LRRK2-related disruption of cilia function. Conclusion In conclusion, we characterized the cellular and extracellular proteome of dopaminergic neurons carrying the LRRK2 G2019S mutation and proposed an experimentally based list of biomarker candidates for future studies.
Harnessing 2D and 3D human endometrial cell culture models to investigate SARS-CoV-2 infection in early pregnancy
2024-12-12

Vertical transmission of SARS-CoV-2 during human pregnancy remains highly controversial as most studies have focused on the third trimester or the peripartum period. Given the lack of early trimester data, determining the prevalence of vertical transmission during early pregnancy and assessing the potential risks for fetal morbidity and mortality pose a challenge. Therefore, we analysed the impact of SARS-CoV-2 infection on an endometrial 3D spheroid model system. The 3D spheroids are capable of decidualization and express angiotensin-converting enzyme 2 (ACE2) as well as transmembrane protease serine 2 (TMPRSS2), rendering them susceptible to SARS-CoV-2 infection. Employing this 3D cell model, we identified that SARS-CoV-2 can infect both non-decidualized and decidualized endometrial spheroids. Infection significantly increased the chemokine Monocyte chemoattractant protein-1 (MCP-1) compared to non-infected spheroids. Decidualized spheroids exhibited upregulated Interleukin (IL)-8 levels. Furthermore, RNA sequencing revealed dysregulation of several genes involved in tissue-specific immune response, Fc receptor signalling, angiotensin-activated signalling and actin function. Gene expression changes varied between SARS-CoV-2 infected non-decidualized and decidualized spheroids and genes associated with the innate immune system (CD38, LCN2 and NR4A3) were dysregulated as a potential mechanism for immune evasion of SARS-CoV-2. Altogether, our study demonstrates that endometrial spheroids are a useful model to examine the clinical implications of SARS-CoV-2 vertical transmission, warranting further investigations.
Influence of the Counterion on the Activation of Nickel(σ-Aryl) Precatalysts
2024-12-12

Complexes of the type LnNi(σ-aryl)Cl are known to be competitive precatalysts for various transformations, avoiding the use of expensive and sensitive Ni(0) precursors, such as Ni(cod)2. The in situ activation requires a transmetalation step with a nucleophile, yielding the active Ni(0) catalyst after reductive elimination. Steric hindrance is usually implemented in the σ-aryl group (e.g. o tolyl or 1 naphthyl) to enhance kinetic stability. Simultaneously, this steric hindrance can render the activation process slow, thus increasing the reaction time and possibly reducing the amount of active catalyst. To circumvent this issue, we envisaged substitution of the anionic chloride ligand of the precatalyst with more labile ligands that would facilitate transmetalation. In this work, a series of (Xantphos)Ni(o-tolyl)X complexes was successfully synthesized and the effect of the counterion X on the reaction profile was investigated using C–S cross-coupling as the model reaction. (Xantphos)Ni(o-tolyl)OTf was identified as the most efficient precatalyst, probably due to the weak coordinating ability of the triflate anion that facilitated the activation step. Finally, this concept was also studied in Suzuki-Miyaura coupling and Buchwald-Hartwig amination reactions using (dppf)Ni(o tolyl)X precatalysts.
Islamic Religious Education in Germany
2024-12-12

The article explores the development and current state of Islamic religious education in Germany. Its origins are rooted in Germany's migration history, particularly the recruitment of guest workers. The increasing integration of Muslims into German society led to political and legal discussions about the introduction of a denominational religious education based on the Basic Law. The focus is on analyzing the legal framework, theological foundations, teacher training, challenges, and future perspectives of Islamic religious education in Germany. The aim is to provide the international readership with a comprehensive overview. The article emphasizes the necessity of an educationally, theologically, and pedagogically sound Islamic religious education. In the long term, Islamic religious education can contribute not only to the religious autonomy of Muslim students but also to fostering a pluralistic society.
Repeated net-tDCS of the hypothalamus appetite-control network reduces inhibitory control and sweet food intake in persons with overweight or obesity
2024-12-12

Background Reduced inhibitory control is associated with obesity and neuroimaging studies indicate that diminished prefrontal cortex activity influence eating behavior and metabolism. The hypothalamus regulates energy homeostasis and is functionally connected to cortical and subcortical regions especially the frontal areas. Objectives We tested network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in appetite control. Methods In a randomized, double-blind parallel group design, 44 adults with overweight or obesity (BMI 30.6 kg/m2, 52.3 % female) received active (anodal or cathodal) or sham 12-channel net-tDCS on the hypothalamus appetite-control network for 25 minutes on three consecutive days while performing a Stop-Signal-Task to measure response inhibition. Before and after stimulation, state questionnaires assessed changes in desire to eat and food craving. Directly after stimulation, participants received a breakfast buffet to evaluate ad-libitum food intake. An oral glucose tolerance test was conducted at follow-up. Resting-state functional MRI was obtained at baseline and follow-up. Results The Stop-Signal Reaction Time (SSRT) was shorter in both active groups versus sham, indicating improved response inhibition. Additionally, a stronger increase in hypothalamic functional connectivity was associated with shorter SSRT. Caloric intake of sweet food was lower in the anodal group versus sham, but no main effects between groups were observed on total and macronutrient intake, food craving ratings and desire to eat. At follow-up, no differences were observed between groups on peripheral metabolism. Conclusion Our study suggests that modulating hypothalamic functional network connectivity patterns via net-tDCS may improve food choice and inhibitory control.
Loom response in mouse superior colliculus depends on sensorimotor context
2024-12-12

Abstract Visual motion is produced both by an organism’s movement through the world, and by objects moving in the world such as potential predators. Choosing appropriate behaviour therefore requires organisms to distinguish these sources of visual motion. Here we asked how mice integrate self-movement with looming visual motion by combining virtual reality and neural recordings from superior colliculus (SC), a brain area important in visually-guided approach and avoidance behaviours. We first measured locomotion behaviour and neural activity while animals approached an object in virtual reality, and while the same object loomed at them. In both cases, vision dominated activity in superficial layers (SCs), while locomotion had more influence on activity in intermediate layers (SCim). In addition, animals instinctively slowed their locomotion when nearing the object, or when the object neared them. To directly test animals’ ability to distinguish self-from object motion we replayed the visual images generated during object approach. Locomotion behaviour often changed during replay, showing animals are able to establish if visual motion is matched to their self-movement. Further, decoders trained on locomotion behaviour, or on population activity in SC, particularly in SCim, were able to reliably discriminate epochs of replay and object approach. We conclude that both mouse behaviour and SC activity encode whether looming visual motion arises from self-or object movement, with implications for understanding sensorimotor coordination in dynamic environments. Highlights We recorded from superficial (SCs) and intermediate (SCim) superior colliculus in VR Vision dominated SCs, while SCim was modulated by both vision and locomotion Mice altered behaviour when visual experience did not match that expected from their locomotion Population activity differed between matched and unmatched visual experiences, particularly in SCim
The mammalian protein MTCH1 can function as an insertase
2024-12-13

Abstract The outer mitochondrial membrane (OMM) hosts a variety of proteins such as import machineries, enzymes, fission/fusion factors, and pore proteins. In Saccharomyces cerevisiae , the MIM complex, consisting of Mim1 and Mim2, mediates the insertion of α-helical proteins into the OMM. Until recently, it was unclear which proteins serve this function in higher eukaryotes. Recent studies identified MTCH2 as the insertase of α-helical proteins into the OMM in mammals. MTCH1 is a paralogue of MTCH2 but its general function and contribution to the biogenesis process are not clear. To better characterize MTCH1, we explored whether MTCH1 or MTCH2 could functionally replace Mim1/Mim2 in yeast. Expression of MTCH1 and MTCH2 in yeast cells lacking Mim1, Mim2, or both revealed that MTCH1, but not MTCH2, could compensate the growth defects upon deleting the MIM complex. Furthermore, MTCH1 could restore the biogenesis of MIM substrates, TOM complex stability, and morphology of mitochondria. These findings indicate that MTCH1 by itself has insertase activity and is a functional homologue of the MIM complex, despite the absence of any evolutionary relation between the mammalian and yeast insertases.
Atheist Thanks to God
2024-12-13

Abstract This paper explores the phenomenon of the non-religious (“nones”) in Latin America by examining the implications of the secular paradox within this population. The secular paradox refers to the tension that secular individuals experience when they engage with religious aspects. Our analysis shows that this tension is a prevalent occurrence in the experience of Latin Americans, nuanced by social representations such as the “atheist thanks to God.” These social imaginaries illustrate the inherent interplay and porosity between the religious and the secular in the region, characterised by its “baroque modernity:” a cultural configuration that both integrates and resists patterns promoted by capitalist and Western modernity. After analysing Latin American nations in terms of the prevalence of religious disaffiliation, the paper focuses on the intersections of the secular and the religious in specific cases such as Mexico and Argentina. The findings indicate that conceptions of religion among our interlocutors are linked to the historical Catholicism of the region, as well as to political secularism, which is both assertive and permeable to religious legitimation. Furthermore, the non-religious tend to purify certain elements of religion, prioritising social bonds while restricting secularism primarily to the intellectual level. By addressing the secular-religious tension among Latin American “nones,” this research contributes to a deeper understanding of secular identity beyond the modernity and secularisation of the Atlantic North.
Neonatal apnea and hypopnea prediction in infants with Robin sequence with neural additive models for time series
2024-12-13

Neonatal apneas and hypopneas present a serious risk for healthy infant development. Treating these adverse events requires frequent manual stimulation by skilled personnel, which can lead to alarm fatigue. This study aims to develop and validate an interpretable model that can predict apneas and hypopneas. Automatically predicting these adverse events before they occur would enable the use of methods for automatic intervention. We propose a neural additive model to predict individual occurrences of neonatal apnea and hypopnea and apply it to a physiological dataset from infants with Robin sequence at risk of upper airway obstruction. The dataset will be made publicly available together with this study. Our proposed model allows the prediction of individual apneas and hypopneas, achieving an average AuROC of 0.80 when discriminating segments of polysomnography recordings starting 15 seconds before the onset of apneas and hypopneas from control segments. Its additive nature makes the model inherently interpretable, which allowed insights into how important a given signal modality is for prediction and which patterns in the signal are discriminative. For our problem of predicting apneas and hypopneas in infants with Robin sequence, prior irregularities in breathing-related modalities as well as decreases in SpO 2 levels were especially discriminative. Our prediction model presents a step towards an automatic prediction of neonatal apneas and hypopneas in infants at risk for upper airway obstruction. Together with the publicly released dataset, it has the potential to facilitate the development and application of methods for automatic intervention in clinical practice.