julilili42/papers huggingface dataset:
Potential Modulation of Inflammation and Physical Function by Combined Probiotics, Omega-3 Supplementation and Vitamin D Supplementation in Overweight/Obese Patients with Chronic Low-Grade Inflammation: A Randomized, Placebo-Controlled Trial
2023-05-10

Obesity is characterized by low-grade inflammation and increased gut permeability. Here, we aim to evaluate the effect of a nutritional supplement on these parameters in subjects with overweight and obesity. A double-blinded, randomized clinical trial was conducted in 76 adults with overweight or obesity (BMI 28 to 40) and low-grade inflammation (high-sensitivity C-reactive protein (hs-CRP) between 2 and 10 mg/L). The intervention consisted of a daily intake of a multi-strain probiotic of Lactobacillus and Bifidobacterium, 640 mg of omega-3 fatty acids (n-3 FAs), and 200 IU of vitamin D (n = 37) or placebo (n = 39), administered for 8 weeks. hs-CRP levels did not change post-intervention, other than an unexpected slight increase observed in the treatment group. Interleukin (IL)-6 levels decreased in the treatment group (p = 0.018). The plasma fatty acid (FA) levels of the arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio and n-6/n-3 ratio (p &lt; 0.001) decreased, and physical function and mobility improved in the treatment group (p = 0.006). The results suggest that hs-CRP may not be the most useful inflammatory marker, but probiotics, n-3 FAs, and vitamin D, as non-pharmaceutical supplements, may exert modest effects on inflammation, plasma FA levels, and physical function in patients with overweight and obesity and associated low-grade inflammation.
Social learning with a grain of salt
2023-05-10

Humans are remarkably effective social learners, with several recent studies formalizing this capacity using computational models. However, previous research has often been limited to tasks where observer and demonstrator share the same reward function. In contrast, humans can learn from others who have different preferences, skills, or goals. To study social learning under individual differences, we introduce the socially correlated bandit, where participants have personalized rewards, which are correlated with but not identical to those of others. Social information can still be useful, but not when used verbatim. We present a model of Social Generalization that integrates individual and social information into the generalization process, but assumes social information to be noisier and thus less informative. This model out-competes previous models, with it being the dominant strategy in evolutionary simulations. Our findings expand on previous models of social learning, showing humans can integrate social information more flexibly than previously assumed.
ChatGPT in Education: Global Reactions to AI Innovations
2023-05-10

Abstract The release and rapid diffusion of ChatGPT have caught the attention of educators worldwide. Some educators are enthusiastic about its potential to support learning, others are concerned about how it might circumvent learning opportunities or contribute to misinformation. To better understand reactions about ChatGPT concerning education, we analyzed Twitter data (16,830,997 tweets from 5,541,457 users). Based on topic modeling and sentiment analysis, we provide an overview of global perceptions and reactions to ChatGPT regarding education. ChatGPT triggered a massive response on Twitter, with education being the most tweeted content topic. Topics ranged from specific (e.g., cheating) to broad (e.g., opportunities), which were discussed with mixed sentiment. We traced that authority decisions can influence public opinions and that the average reaction on Twitter differs from scientific discussions. This study provides insights into people's reactions when new groundbreaking technology is released and implications for scientific and policy communication in rapidly changing circumstances.
Bi-allelic variants of FILIP1 cause congenital myopathy, dysmorphism and neurological defects
2023-05-10

Abstract Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology.
Chronology of detrital carbonate events in Baffin Bay reveals different timing but similar average recurrence time of North American-Arctic and Laurentide ice sheet collapse events during MIS 3
2023-05-10

Baffin Bay Detrital Carbonate (BBDC) layers represent periods of elevated discharge of terrigenous sediments, icebergs and freshwater originating from the North American Arctic-ice sheet complex. Distinct from Heinrich event layers in their dolomitic composition, these sedimentary deposits are found throughout Baffin Bay. They are considered a signature of large-scale instability of the ice sheets discharging into the Baffin Bay, akin to the Heinrich events of the North Atlantic. However, the precise timing of and potential forcing mechanisms for the North American Arctic-ice sheet instabilities remains elusive. Previous work suggests that BBDC events were not in phase with Heinrich events originating from the Hudson Strait, but this hypothesis could not be tested without rigorous chronological constraints. By combining radiocarbon ages and relative paleointensity (RPI) dating in a central western Baffin Bay marine sedimentary sequence, we were able to derive a new chronology for BBDC events covering a large part of MIS3. Sedimentological and elemental data indicate the occurrence of seven distinct BBDC events over the last 52 ka. These events occur during both glacials (stadials) and interglacials (interstadials) and have no consistent phase relationship with Heinrich events. However, the mean duration and mean recurrence time of BBDC events appears similar to Heinrich events. We conclude that BBDC events reflect repeated ice sheet instability periods, with similar statistical properties but different timing compared to the Heinrich events. This implies that episodic instability was an intrinsic property of the North American Arctic-ice sheet complex as well, but over the studied period of MIS3, instabilities of the Arctic and the Laurentide Ice sheets did not appear to have been linked.
Ethical Issues in Cerebral Organoid Research
2023-05-10

About ten years ago, reports of lab-grown “mini brains” or “brains in a dish” appeared in the media, falling somewhere between the curious and the alarming. The trigger of these reports was a new method to grow three-dimensional neural tissue from human stem cells that recapitulates, to some degree, the early development of brain tissue. Despite their relatively small size and other limitations, such model systems capture in part the structure and functions of regions of the human brain and can also be combined to form so-called assembloids.
The Structural Combination of SIL and MODAG Scaffolds Fails to Enhance Binding to α-Synuclein but Reveals Promising Affinity to Amyloid β
2023-05-10

A technique to image α-synuclein (αSYN) fibrils in vivo is an unmet scientific and clinical need that would represent a transformative tool in the understanding, diagnosis, and treatment of various neurodegenerative diseases. Several classes of compounds have shown promising results as potential PET tracers, but no candidate has yet exhibited the affinity and selectivity required to reach clinical application. We hypothesized that the application of the rational drug design technique of molecular hybridization to two promising lead scaffolds could enhance the binding to αSYN up to the fulfillment of those requirements. By combining the structures of SIL and MODAG tracers, we developed a library of diarylpyrazoles (DAPs). In vitro evaluation through competition assays against [3H]SIL26 and [3H]MODAG−001 showed the novel hybrid scaffold to have preferential binding affinity for amyloid β (Aβ) over αSYN fibrils. A ring-opening modification on the phenothiazine building block to produce analogs with increased three-dimensional flexibility did not result in an improved αSYN binding but a complete loss of competition, as well as a significant reduction in Aβ affinity. The combination of the phenothiazine and the 3,5-diphenylpyrazole scaffolds into DAP hybrids did not generate an enhanced αSYN PET tracer lead compound. Instead, these efforts identified a scaffold for promising Aβ ligands that may be relevant to the treatment and monitoring of Alzheimer’s disease (AD).
Anatomical and behavioral correlates of auditory perception in developmental dyslexia
2023-05-10

Abstract Developmental dyslexia is typically associated with difficulties in basic auditory processing and in manipulating speech sounds. However, the neuroanatomical correlates of auditory difficulties in developmental dyslexia (DD) and their contribution to individual clinical phenotypes are still unknown. Recent intracranial electrocorticography findings associated processing of sound amplitude rises and speech sounds with posterior and middle superior temporal gyrus (STG), respectively. We hypothesize that regional STG anatomy will relate to specific auditory abilities in DD, and that auditory processing abilities will relate to behavioral difficulties with speech and reading. One hundred and ten children (78 DD, 32 typically developing, age 7-15 years) completed amplitude rise time and speech in noise discrimination tasks. They also underwent a battery of cognitive tests. Anatomical MRI scans were used to identify regions in which local cortical gyrification complexity correlated with auditory behavior. Behaviorally, amplitude rise time but not speech in noise performance was impaired in DD. Neurally, amplitude rise time and speech in noise performance correlated with gyrification in posterior and middle STG, respectively. Furthermore, amplitude rise time significantly contributed to reading impairments in DD, while speech in noise only explained variance in phonological awareness. Finally, amplitude rise time and speech in noise performance were not correlated, and each task was correlated with distinct neuropsychological measures, emphasizing their unique contributions to DD. Overall, we provide a direct link between the neurodevelopment of the left STG and individual variability in auditory processing abilities in neurotypical and dyslexic populations.
Effects of Equine-Assisted Therapy on Recovery after Stroke – A Systematic Review
2023-05-10

Abstract Background Equine-Assisted Therapy (EAT) can boost well-being and recovery of patients with neurological or psychiatric disorders. Objective The goal of this systematic review is to gain a better understanding of the effects of EAT on recovery after stroke. Methods A systematic literature search was performed in the following databases: PubMed, Web of Science and Scopus. Furthermore, reference lists from the articles included were screened. English-written articles published between 2000-2023 that reported on health-related effects of EAT (applied with both horses and riding simulators) on stroke recovery in patients aged between 18 and 85 were included. Methodological quality was assessed by the Mixed Methods Appraisal Tool. Results Following the screening of 2030 and retrieval of 33 articles respectively, 14 studies were included in this systematic review (437 patients, mean age range: 40 – 70 years). Since several of these studies lacked important methodological information, the overall methodological quality varied. Thirteen studies reported physical findings (balance, gait, postural coordination, activities of daily living, lower extremity motor impairment, motor function and hand strength), and seven studies reported further health-related outcomes (cognition, quality of life, depression and perception of the intervention, muscle thickness and trunk muscle activity). The findings suggest positive effects of EAT on stroke recovery in different health-related outcomes, whereas the most consistent beneficial effects were reported for balance and gait. Conclusion EAT appears to be a promising multimodal intervention for the recovery of different functions after stroke. However, evidence is sparse and methodological quality limited. Future research should investigate the effects of EAT on stroke recovery more systematically.
Electronic appendix to: Organic matter matters - The imaginary conductivity of sediments rich in solid organic carbon
2023-05-10

&lt;p&gt;This is the electronic appendix to the publication&nbsp;&lt;/p&gt; &lt;p&gt;C.Strobel, M. Doerrrich, E.-H. Stieff, J. A. Huisman, O.A. Cirpka, A. Mellage (2023):&nbsp;Organic matter matters - The imaginary conductivity of sediments rich in solid organic carbon&nbsp;(submitted)&lt;/p&gt; &lt;p&gt;&nbsp;&lt;/p&gt;
GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response
2023-05-11

Abstract Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA-FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA-FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n-of-1 treatment studies. GAA-FGF14 ataxia consistently presented as late-onset [60.0 years (53.5–68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA-FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n-of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA-FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia.
Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor–Positive/ERBB2-Positive Early Breast Cancer
2023-05-11

Importance Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ ERBB2 -positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ ERBB2 -positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ ERBB2 -positive EBC. Design, Setting, and Participants This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor–positive and/or progesterone receptor–positive (&amp;amp;gt;1%) HR-positive/ ERBB2 -positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m 2 , weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P &amp;amp;lt; .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2 -enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ ERBB2 -positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration ClinicalTrials.gov Identifier: NCT03272477
Physiologically‐based pharmacokinetic modeling of quinidine to establish a CYP3A4, P‐gp, and CYP2D6 drug–drug–gene interaction network
2023-05-11

Abstract The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) and is therefore recommended for use in clinical drug–drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P‐gp, it is susceptible to DDIs involving these proteins. Physiologically‐based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug–drug(–gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P‐gp perpetrators as well as CYP2D6 and P‐gp victims. The quinidine parent‐metabolite model including 3‐hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1–600 mg). The model covers efflux transport via P‐gp and metabolic transformation to either 3‐hydroxyquinidine or unspecified metabolites via CYP3A4. The 3‐hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two‐fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two‐fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is.
Compositionality Under Time Pressure
2023-05-11

Compositionality is a central component of the human faculty for generalization and flexibility. However, the computations involved are poorly understood, especially in terms of their cognitive costs. On one hand, compositionality requires searching combinatorially large hypothesis spaces, raising issues of tractability.On the other hand, compositional representations afford efficient and compact compression. To shed light on the cognitive resource required for compositionality, we used a within-subject time pressure manipulation to study how participants navigated a series of mazes, generated using recursive operations over spatial primitives. We find evidence that behavior is guided by the use of primitives and abstract operations over them, where the degree of compositional structure increases performance and speeds up decisions.And while time pressure led to more random errors, it did not impair the capacity for compositionality. Rather, participants increased their reliance on reusing and recombining previous computations, suggesting a remarkable robustness of human compositional reasoning.
What Predicts AI Usage? Investigating the Main Drivers of AI Use Intention over Different Contexts
2023-05-11

Artificial Intelligence (AI) based applications are an ever-expanding field, with an increasing number of sectors deploying this technology. While previous research often focused on understanding AI usage in one domain, we aimed to investigate the main drivers of AI usage over a broad range of contexts. To this end, we conducted two studies (N = 450, representative for age and gender; N = 259, balanced for age and gender) covering a wide range of contexts (e.g., medical, autonomous driving, art), assessing well-established variables in AI research (trust, familiarity, attitudes) as well as AI aversion, knowledge about AI, and risk-opportunity perception. We further investigated the influence of AI use-related ratings (i.e. context-specific opinions of AI) on AI usage. Generally, higher trust in AI, more positive use-related ratings, and lower risk perception significantly predict general AI usage intention. Additionally, both studies revealed that willingness to use AI varied significantly depending on the context. These findings highlight the relevance of trust, risk-opportunity perception, and use-related ratings in understanding laypeople’s general intention to use AI-based applications while at the same time emphasizing the importance of taking context into account.