julilili42/papers huggingface dataset:
Untargeted stable isotope-resolved metabolomics to assess the effect of PI3Kβ inhibition on metabolic pathway activities in a PTEN null breast cancer cell line
2022-10-14

The combination of high-resolution LC-MS untargeted metabolomics with stable isotope-resolved tracing is a promising approach for the global exploration of metabolic pathway activities. In our established workflow we combine targeted isotopologue feature extraction with the non-targeted X 13 CMS routine. Metabolites, detected by X 13 CMS as differentially labeled between two biological conditions are subsequently integrated into the original targeted library. This strategy enables monitoring of changes in known pathways as well as the discovery of hitherto unknown metabolic alterations. Here, we demonstrate this workflow in a PTEN (phosphatase and tensin homolog) null breast cancer cell line (MDA-MB-468) exploring metabolic pathway activities in the absence and presence of the selective PI3Kβ inhibitor AZD8186. Cells were fed with [U- 13 C] glucose and treated for 1, 3, 6, and 24 h with 0.5 μM AZD8186 or vehicle, extracted by an optimized sample preparation protocol and analyzed by LC-QTOF-MS. Untargeted differential tracing of labels revealed 286 isotope-enriched features that were significantly altered between control and treatment conditions, of which 19 features could be attributed to known compounds from targeted pathways. Other 11 features were unambiguously identified based on data-dependent MS/MS spectra and reference substances. Notably, only a minority of the significantly altered features (11 and 16, respectively) were identified when preprocessing of the same data set (treatment vs. control in 24 h unlabeled samples) was performed with tools commonly used for label-free (i.e. w/o isotopic tracer) non-targeted metabolomics experiments (Profinder ́s batch recursive feature extraction and XCMS). The structurally identified metabolites were integrated into the existing targeted isotopologue feature extraction workflow to enable natural abundance correction, evaluation of assay performance and assessment of drug-induced changes in pathway activities. Label incorporation was highly reproducible for the majority of isotopologues in technical replicates with a RSD below 10%. Furthermore, inter-day repeatability of a second label experiment showed strong correlation (Pearson R 2 &amp;gt; 0.99) between tracer incorporation on different days. Finally, we could identify prominent pathway activity alterations upon PI3Kβ inhibition. Besides pathways in central metabolism, known to be changed our workflow revealed additional pathways, like pyrimidine metabolism or hexosamine pathway. All pathways identified represent key metabolic processes associated with cancer metabolism and therapy.
Fear memory in humans is consolidated over time independently of sleep
2022-10-14

Abstract Fear memories can be altered after acquisition by processes, such as fear memory consolidation or fear extinction, even without further exposure to the fear-eliciting stimuli, but factors contributing to these processes are not well understood. Sleep is known to consolidate, strengthen, and change newly acquired declarative and procedural memories. However, evidence on the role of time and sleep in the consolidation of fear memories is inconclusive. We used highly sensitive electrophysiological measures to examine the development of fear-conditioned responses over time and sleep in humans. We assessed event-related brain potentials (ERP) in 18 healthy, young individuals during fear conditioning before and after a 2-hour afternoon nap or a corresponding wake interval in a counterbalanced within-subject design. The procedure involved pairing a neutral tone (CS+) with a highly unpleasant sound. As a control, another neutral tone (CS−) was paired with a neutral sound. Fear responses were examined before the interval during a habituation phase and an acquisition phase as well as after the interval during an extinction phase and a reacquisition phase. Differential fear conditioning during acquisition was evidenced by a more negative slow ERP component (stimulus-preceding negativity) developing before the unconditioned stimulus (loud noise). This differential fear response was even stronger after the interval during reacquisition compared with initial acquisition, but this effect was similarly pronounced after sleep and wakefulness. These findings suggest that fear memories are consolidated over time, with this effect being independent of intervening sleep.
Thalamocortical networks involved in Pusher Syndrome
2022-10-14

Abstract Indirect quantification of functional and structural disconnection increases the knowledge derived from focal brain lesions by inferring subsequent brain network damage from the respective lesion. We applied both measures to a sample of 124 stroke patients to investigate brain disconnection in pusher syndrome – a disorder characterized by a disturbed perception of one’s own upright body posture. Our results suggest a hub-like function of the posterior and lateral portions of the thalamus in the perception of one’s own postural upright and identified dysfunction in a thalamo-cortical network as one likely cause of pusher syndrome. Lesion network-symptom-mapping investigating functional disconnection indicated cortical diaschisis in cerebellar, frontal, parietal, occipital, and temporal areas in patients with thalamic lesions suffering from pusher syndrome, but there was no evidence for functional diaschisis in cortical stroke and no evidence for the convergence of thalamic and cortical lesions onto a common functional network. Structural disconnectivity mapping identified several thalamo-cortical disconnections. Many of the thalamic and cortical regions disconnected by lesions that lead to pusher behavior correspond to previously reported lesion sites associated with pusher syndrome. Thus, while the presence of both, isolated thalamic and cortical lesions in context with pusher behavior has been reported previously and led to the conclusion that the correct estimation of one’s own postural upright might depend on a thalamo-cortical network, our analyses offer the first evidence for a direct thalamo-cortical (or cortico-thalamic) interconnection and, more importantly, shed light on the location of the respective thalamo-cortical disconnections.
Memory for abstract Control States does not decay with increasing retrieval delays
2022-10-14

Abstract Recent studies have suggested that abstract control-states (i.e., internal attentional states independent from concrete stimuli and responses) can be stored in episodic memory and retrieved subsequently. However, the duration of such a control-state memory remains unclear. Previous research has found a quick and complete decay for stimulus-response bindings after 2000–5000 ms. Here, we tested a possible decay of control-state bindings with retrieval-delays of 2000, 3000, or 5000 ms. Five preregistered experiments used a confound-minimized prime-target task to measure the congruency sequence effect (CSE) separately for trials in which a nominally irrelevant context feature changed or repeated across trials. Analyses of the individual experiments did not result in conclusive evidence. A mega analysis integrating the data of all experiments ( N total = 326) replicated evidence for binding and retrieval of control-states, in that larger CSEs were found for context repetition trials. Importantly, Bayesian analysis indicated that this effect was not modulated by the length of retrieval delay. While this finding suggests that bindings of abstract control-states can be relatively robust, we also discuss possible limitations of the present research.
Efficacy and safety of osimertinib for patients with EGFR-mutated NSCLC: a systematic review and meta-analysis of randomized controlled studies
2022-10-14

Osimertinib is a recently approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR-T790M resistance mutations. The aim of the present meta-analysis was to investigate the efficacy and safety of osimertinib for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Databases were searched for randomized controlled studies that reported the efficacy and safety of osimertinib versus other treatments (chemotherapy, other EGFR-TKIs, etc.) in treating EGFR-mutated NSCLC. The measured effects included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), central nervous system progression-free survival (CNS-PFS), and overall survival (OS). Additional outcome was the incidence of adverse event. Relative risk (RR) for incidence and hazard ratio (HR) for survival outcomes were pooled. Seven studies containing 3335 participants were finally included. Osimertinib tended to improve ORR and DCR (RRs &gt;1) as compared with other treatments. Osimertinib was also a significant protective factor for PFS, CNS-PFS, and OS (HRs &lt;1 and <i>p</i> &lt; .05). Osimertinib showed similar advantages in improving tumor response and patient survival when used as first-line, second-line, and third-line/adjuvant therapy, respectively, as compared with other treatments (RRs &gt;1 for ORR and DCR; HRs &lt;1 for PFS, CNS-PFS, and OS). Osimertinib also had better therapeutic effects as compared with chemotherapy, other EGFR TKIs, docetaxel + bevacizumab, and placebo, respectively. The five most common adverse events with pooled incidence &gt; 20% were diarrhea, rash, nail effects, dry skin, and stomatitis, yet the pooled incidence of serious adverse events was less than 2%. This meta-analysis suggests that osimertinib has a positive effect in disease control and survival for patients with EGFR-mutated NSCLC with acceptable toxicities.
Rewiring of the protein–protein–metabolite interactome during the diauxic shift in yeast
2022-10-15

Abstract In budding yeast Saccharomyces cerevisiae , the switch from aerobic fermentation to respiratory growth is separated by a period of growth arrest, known as the diauxic shift, accompanied by a significant metabolic rewiring, including the derepression of gluconeogenesis and the establishment of mitochondrial respiration. Previous studies reported hundreds of proteins and tens of metabolites accumulating differentially across the diauxic shift transition. To assess the differences in the protein–protein (PPIs) and protein–metabolite interactions (PMIs) yeast samples harvested in the glucose-utilizing, fermentative phase, ethanol-utilizing and early stationary respiratory phases were analysed using isothermal shift assay (iTSA) and a co-fractionation mass spectrometry approach, PROMIS. Whereas iTSA monitors changes in protein stability and is informative towards protein interaction status, PROMIS uses co-elution to delineate putative PPIs and PMIs. The resulting dataset comprises 1627 proteins and 247 metabolites, hundreds of proteins and tens of metabolites characterized by differential thermal stability and/or fractionation profile, constituting a novel resource to be mined for the regulatory PPIs and PMIs. The examples discussed here include (i) dissociation of the core and regulatory particle of the proteasome in the early stationary phase, (ii) the differential binding of a co-factor pyridoxal phosphate to the enzymes of amino acid metabolism and (iii) the putative, phase-specific interactions between proline-containing dipeptides and enzymes of central carbon metabolism.
Hepatobiliary Thyroid Hormone Deficiency Impacts Bile Acid Hydrophilicity and Aquaporins in Cholestatic C57BL/6J Mice
2022-10-15

Women are more prone to develop either hypothyroidism or cholesterol gallstones than men. However, a male predominance in cholesterol gallstones under hypothyroidism was reported. Recently, a novel pathogenic link between thyroid hormone (TH) deficiency and cholesterol gallstones has been described in male mice. Here, we investigate if TH deficiency impacts cholesterol gallstone formation in females by the same mechanism. Three-month-old C57BL/6J mice were randomly divided into a control, a TH deficient, a lithogenic, and a lithogenic + TH deficient group and diet-treated for two, four, and six weeks. Gallstone prevalence, liver function tests, bile composition, hepatic gene expression, and gallbladder aquaporin expression and localization were investigated. Cholesterol gallstones were observed in lithogenic + TH deficient but not lithogenic only female mice. Diminished hydrophilicity of primary bile acids due to decreased gene expression of hepatic detoxification phase II enzymes was observed. A sex-specific expression and localization of hepatobiliary aquaporins involved in transcellular water and glycerol permeability was observed under TH deficient and lithogenic conditions. TH deficiency promotes cholesterol gallstone formation in female C57BL/6J mice by the same mechanism as observed in males. However, cholesterol gallstone prevalence was lower in female than male C57BL/6J mice. Interestingly, the sex-specific expression and localization of hepatobiliary aquaporins could protect female C57BL/6J mice to cholestasis and could reduce biliary water transport in male C57BL/6J mice possibly contributing to the sex-dependent cholesterol gallstone prevalence under TH deficiency.
Cuprizone feeding induces swollen astrocyte endfeet
2022-10-15

Abstract The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is mainly being used to study demyelination and the mechanisms of remyelination, as well as the efficiency of compounds or therapeutics aiming at remyelination. Although early investigations using high dosages of cuprizone reported the occurrence of hydrocephalus, it has long been assumed that cuprizone feeding at lower dosages does not induce changes at the blood–brain barrier (BBB). Here, by analyzing BBB ultrastructure with high-resolution electron microscopy, we report changes at astrocytic endfeet surrounding vessels in the brain parenchyma. Particularly, edema formation around blood vessels and swollen astrocytic endfeet already occurred after feeding low dosages of cuprizone. These findings indicate changes in BBB function that will have an impact on the milieu of the central nervous system (CNS) in the cuprizone model and need to be considered when studying the mechanisms of de- and remyelination.
The Association between Constitutional Knee Alignment and the Horizontal Orientation of the Ankle Joint Line
2022-10-15

PURPOSE OF THE STUDY To characterize constitutional frontal alignment of the ankle in genua vara, valga, and norma. MATERIAL AND METHODS Long-leg standing radiographs of 589 patients presenting between 2011 and 2020 for knee-complaints because of any reason were chosen from our database. Cases with fractures or history of bony-realignment-surgeries were excluded. The Hip-Knee-Ankle angle (HKA), the mechanical Lateral Distal Tibia Angle (mLDTA), and the Tibia-Plafond-Horizontal-Orientation angle (TPHA) were measured in 354 patients. For this study, neutral frontal alignment of the leg was defined as HKA between -3.0° and +4.0°. HKA-values <-3.0° were defined as genua valga and values >4.0° were defined as genua vara. According to these cutoffs, data was categorized into the following three patient groups: genua vara (n=157), genua norma (n=106), genua valga (n=91). For each group, the ankle alignment in the frontal plane was compared to the HKA. Finally, the three groups were compared to each other. RESULTS In the varus-group, the HKA-value was 6.9°±2.4°, the TPHA-value was 4.7°±3.5°, and the mLDTA-value was 87.4°±4.8°. In the neutral-group, the HKA-value was 1.8°±2.0°, the TPHA-value was 2.5°±2.9°, and the mLDTA-value was 87.2°±4.6°. In the valgus-group, the HKA-value was -6.0°±2.7°, the TPHA-value was -0.2°±4.7°, and the mLDTA-value was 85.0°±4.7°. DISCUSSION The frontal alignment of the ankle joint line depends on the overall frontal alignment of the leg. The TPHA correlates with varus or valgus alignment of the knee, but the mLDTA does not. In patients with valgus-aligned long-leg axis, the TPHA demonstrated less valgus alignment than in patients with varus-aligned long-leg axis. This knowledge is especially useful when planning osteotomies for correction of lower extremity malalignment. CONCLUSIONS During the planning process of osteotomies around the knee, the TPHA should be appreciated because it correlates with the constitutional knee alignment. Key words: valgus, varus, frontal alignment, coronal alignment, osteotomy.
Change Detection for Local Explainability in Evolving Data Streams
2022-10-16

As complex machine learning models are increasingly used in sensitive applications like banking, trading or credit scoring, there is a growing demand for reliable explanation mechanisms. Local feature attribution methods have become a popular technique for post-hoc and model-agnostic explanations. However, attribution methods typically assume a stationary environment in which the predictive model has been trained and remains stable. As a result, it is often unclear how local attributions behave in realistic, constantly evolving settings such as streaming and online applications. In this paper, we discuss the impact of temporal change on local feature attributions. In particular, we show that local attributions can become obsolete each time the predictive model is updated or concept drift alters the data generating distribution. Consequently, local feature attributions in data streams provide high explanatory power only when combined with a mechanism that allows us to detect and respond to local changes over time. To this end, we present CDLEEDS, a flexible and model-agnostic framework for detecting local change and concept drift. CDLEEDS serves as an intuitive extension of attribution-based explanation techniques to identify outdated local attributions and enable more targeted recalculations. In experiments, we also show that the proposed framework can reliably detect both local and global concept drift. Accordingly, our work contributes to a more meaningful and robust explainability in online machine learning.
Motivations and Specialization of Birders Are Differently Related to Engagement in Citizen Science Projects of Different Complexity
2022-10-16

Citizen Science (CS) projects are an important aspect of scientific data collection and biodiversity conservation. In ornithology, various CS projects exist, and even laypersons can contribute, but advanced birdwatchers also spend considerable time and effort in data collection. Here, different CS projects for birders were analyzed and compared with respect to recreation specialization and motivations for birdwatching. Established, psychometrically valid, and reliable scales were applied in this study. N = 2856 respondents from Austria, Germany, and Switzerland were grouped into no, low, and sustained engagement clusters. Sustained engagement was related to more complex programs, such as the breeding bird census and waterfowl counting. When comparing the engagement clusters, effect sizes were considerable, ranging from 0.098 (attraction) to 0.306 (skill/knowledge). Thus, birders of the three engagement clusters differed significantly in birding specialization, especially skill/knowledge, psychological commitment, social motivations, and the psychological construct centrality to lifestyle. No differences were found in enjoyment and achievement motivations. In conclusion, low-threshold projects are needed to attract participants, but keeping people within programs or moving them to a higher level of engagement might be easier when social dimensions are addressed.
Physiological Offset Parameters of the Adult Shoulder Joint—A MRI Study of 800 Patients
2022-10-16

Background: Humeral offset (HO) and glenoidal offset (GO) are important morphological parameters in diagnostics and therapy for shoulder pathologies. However, physiological reference values have not yet been sufficiently determined. The aim of the present study was to establish physiological reference values for shoulder offset parameters (SOPs). Methods: MRI images of the shoulder joints of 800 patients (mean age: 50.13 years [±16.01]) were analysed retrospectively. HO, GO, lateral glenoidal humeral offset (LGHO), humeral shaft axis offset (HAO) and cortical offset (CO) were measured. SOPs were examined for associations with age, gender, side and osteoarthritis. Results: The mean HO was 26.19 (±2.70), the mean GO was 61.79 (±5.67), the mean LGHO was 54.49 (±4.69), the mean HAO was 28.17 (±2.82) and the mean CO was 16.70 (±3.08). For all SOPs, significantly higher values were measured in male shoulders. There was a significantly (p &lt; 0.001) higher mean value for HO, GO and LGHO in right shoulders. There was a significant correlation between age and LGHO, and HAO and CO, but not between age and HO or GO. Shoulders with osteoarthritis and non-osteoarthritis did not differ in the mean value of HO, GO, LGHO and HAO, except for CO (p = 0.049). Conclusion: Reference values for SOPs in the adult shoulder joint were determined for the first time. Significant gender-specific differences were found for all measured SOPs. In addition, it was seen that for some SOPs, the joint side and the patient’s age has to be taken into account in shoulder diagnostics and surgery.
Performance Evaluation of the Schistoscope 5.0 for (Semi-)automated Digital Detection and Quantification of Schistosoma haematobium Eggs in Urine: A Field-based Study in Nigeria
2022-10-17

ABSTRACT. Conventional microscopy is the standard procedure for the diagnosis of schistosomiasis, despite its limited sensitivity, reliance on skilled personnel, and the fact that it is error prone. Here, we report the performance of the innovative (semi-)automated Schistoscope 5.0 for optical digital detection and quantification of Schistosoma haematobium eggs in urine, using conventional microscopy as the reference standard. At baseline, 487 participants in a rural setting in Nigeria were assessed, of which 166 (34.1%) tested S. haematobium positive by conventional microscopy. Captured images from the Schistoscope 5.0 were analyzed manually (semiautomation) and by an artificial intelligence (AI) algorithm (full automation). Semi- and fully automated digital microscopy showed comparable sensitivities of 80.1% (95% confidence interval [CI]: 73.2–86.0) and 87.3% (95% CI: 81.3–92.0), but a significant difference in specificity of 95.3% (95% CI: 92.4–97.4) and 48.9% (95% CI: 43.3–55.0), respectively. Overall, estimated egg counts of semi- and fully automated digital microscopy correlated significantly with the egg counts of conventional microscopy ( r = 0.90 and r = 0.80, respectively, P &lt; 0.001), although the fully automated procedure generally underestimated the higher egg counts. In 38 egg positive cases, an additional urine sample was examined 10 days after praziquantel treatment, showing a similar cure rate and egg reduction rate when comparing conventional microscopy with semiautomated digital microscopy. In this first extensive field evaluation, we found the semiautomated Schistoscope 5.0 to be a promising tool for the detection and monitoring of S. haematobium infection, although further improvement of the AI algorithm for full automation is required.