Miracle-dz/UniFAR-FTUs huggingface dataset:
Triad pyrazole–thiazole–coumarin heterocyclic core effectively inhibit HSP and drive cancer cells to apoptosis

Abstract Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole–Thiazol–Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds (PTC10) implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment. Communicated by Ramaswamy H. Sarma
The role of gestures in autobiographical memory

Speakers employ co-speech gestures when thinking and speaking; however, gesture’s role in autobiographical episodic representations is not known. Based on the gesture-for-conceptualization framework, we propose that gestures, particularly representational ones, support episodic event representations by activating existing episodic elements and causing new ones to be formed in the autobiographical recollections. These gestures may also undertake information-chunking roles to allow for further processing during remembering, such as a sense of recollective experience. Participants (N = 41) verbally narrated three events (a past autobiographical, a future autobiographical, and a non-autobiographical event) and then rated their phenomenological characteristics. We found that, even though gesture use was not different across the three event conditions, representational gestures were positively associated with the episodic event details as well as their recollective quality within the past autobiographical event narratives. These associations were not observed in future event narrations. These findings suggest that gestures are potentially instrumental in the retrieval of details in autobiographical memories.
Optimizing hierarchical tree dissection parameters using historic epidemiologic data as ‘ground truth’

Hierarchical clustering of pathogen genotypes is widely used to complement epidemiologic investigations of outbreaks. Investigators must dissect trees to obtain genetic partitions that provide epidemiologists with meaningful information. Statistical approaches to tree dissection often require a user-defined parameter to predict the optimal partition number and augmenting this parameter can drastically impact resultant partition memberships. Here, we demonstrate how to optimize a given tree dissection parameter to maximize accuracy irrespective of the tree dissection method used. We hierarchically clustered 1,873 genotypes of the foodborne pathogen Cyclospora spp. , including 587 possessing links to historic outbreaks. We dissected the resulting tree using a statistical method requiring users to select the value of a ‘stringency parameter’ (s), with a recommended value of 95% to 99.5%. We dissected this hierarchical tree across s-values from 94% to 99.5% (at increments of 0.25%), to identify a value that maximized partitioning accuracy, defined as the degree to which genetic partitions conform to known epidemiologic groupings. We show that s-values of 96.5% and 96.75% yield the highest accuracy (> 99.9%) when clustering Cyclospora sp. isolates with known epidemiologic linkages. In practice, the optimized s-value will generate robust genetic partitions comprising isolates likely derived from a common food source, even when the epidemiologic grouping is not known prior to genetic clustering. While the s-value is specific to the tree dissection method used here, the optimization approach described could be applied to any parameter/method used to dissect hierarchical trees.
Effects of helminths and anthelmintic treatment on cardiometabolic diseases and risk factors: A systematic review

Background Globally, helminth infections and cardiometabolic diseases often overlap in populations and individuals. Neither the causal relationship between helminth infections and cardiometabolic diseases nor the effect of helminth eradication on cardiometabolic risk have been reviewed systematically in a large number of human and animal studies. Methods We conducted a systematic review assessing the reported effects of helminth infections and anthelmintic treatment on the development and/or severity of cardiometabolic diseases and risk factors. The search was limited to the most prevalent human helminths worldwide. This study followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42021228610). Searches were performed on December 10, 2020 and rerun on March 2, 2022 using Ovid MEDLINE ALL (1946 to March 2, 2022), Web of Science, Cochrane Library, Global Index Medicus, and Ovid Embase (1974 to March 2, 2022). Randomized clinical trials, cohort, cross-sectional, case-control, and animal studies were included. Two reviewers performed screening independently. Results Eighty-four animal and human studies were included in the final analysis. Most studies reported on lipids (45), metabolic syndrome (38), and diabetes (30), with fewer on blood pressure (18), atherosclerotic cardiovascular disease (11), high-sensitivity C-reactive protein (hsCRP, 5), and non-atherosclerotic cardiovascular disease (4). Fifteen different helminth infections were represented. On average, helminth-infected participants had less dyslipidemia, metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease. Eleven studies examined anthelmintic treatment, of which 9 (82%) reported post-treatment increases in dyslipidemia, metabolic syndrome, and diabetes or glucose levels. Results from animal and human studies were generally consistent. No consistent effects of helminth infections on blood pressure, hsCRP, or cardiac function were reported except some trends towards association of schistosome infection with lower blood pressure. The vast majority of evidence linking helminth infections to lower cardiometabolic diseases was reported in those with schistosome infections. Conclusions Helminth infections may offer protection against dyslipidemia, metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease. This protection may lessen after anthelmintic treatment. Our findings highlight the need for mechanistic trials to determine the pathways linking helminth infections with cardiometabolic diseases. Such studies could have implications for helminth eradication campaigns and could generate new strategies to address the global challenge of cardiometabolic diseases.
Exploring impaired self-awareness of motor symptoms in Parkinson’s disease: Resting-state fMRI correlates and the connection to mindfulness

Objective To further explore the phenomenon of impaired self-awareness of motor symptoms in patients with Parkinson’s Disease by using an evaluated measurement approach applied in previous studies, while also examining its connection with dispositional mindfulness and possible correlates of functional connectivity. Background Recently, the phenomenon of impaired self-awareness has been studied more intensively by applying different measurement and imaging methods. Existing literature also points towards a possible connection with mindfulness, which has not been examined in a cross-sectional study. There is no data available concerning correlates of functional connectivity. Methods Non-demented patients with idiopathic Parkinson’s Disease without severe depression were tested for impaired self-awareness for motor symptoms following a psychometrically evaluated approach. Mindfulness was measured by applying the German version of the Five Facet Mindfulness Questionnaire. A subset of eligible patients underwent functional MRI scanning. Spearman correlation analyses were performed to examine clinical data. Whole-brain voxelwise regressions between seed-based connectivity and behavioral measures were calculated to identify functional connectivity correlates of impaired self-awareness scores. Results A total of 41 patients with Parkinson’s Disease were included. 15 patients successfully underwent resting-state fMRI scanning. Up to 88% of patients showed signs of impaired self-awareness. Awareness for hypokinetic movements correlated with total mindfulness values and three facets, while awareness for dyskinetic movements did not. Three significant clusters between scores of impaired self-awareness in general and for dyskinetic movements were identified linking behavioral measures with the functional connectivity of the inferior frontal gyrus, the right insular cortex, the supplementary motor area, and the precentral gyrus among others. Impaired self-awareness for hypokinetic movements did not have any neural correlate. Conclusions Clinical data is comparable with results from previous studies applying the same structured approach to measure impaired self-awareness in Parkinson’s Disease. Functional connectivity analyses were conducted for the first time to evaluate neural correlates thereof. This data does not support a connection between impaired self-awareness of motor symptoms and dispositional mindfulness.
The interaction between physical frailty and prognostic impact of heart failure medication in elderly patients

Frailty is highly prevalent and associated with poor prognoses in elderly patients with heart failure (HF). However, the potential effects of physical frailty on the benefits of HF medications in elderly patients with HF are unclear. We aimed to determine the influence of physical frailty on the prognosis of HF medications in elderly patients with HF with reduced and mildly reduced ejection fraction (HFr/mrEF).
Multispectral image denoising by well-posed anisotropic diffusion scheme with channel coupling

A novel way to denoise multispectral images is proposed via an anisotropic diffusion based partial differential equation (PDE). A coupling term is added to the divergence term and it facilitates the modelling of interchannel relations in multidimensional image data. A total variation function is used to model the intrachannel smoothing and gives a piecewise smooth result with edge preservation. The coupling term uses weights computed from different bands of the input image and balances the interchannel information in the diffusion process. It aligns edges from different channels and stops the diffusion transfer using the weights. Well-posedness of the PDE is proved in the space of bounded variation functions. Comparison with the previous approaches is provided to demonstrate the advantages of the proposed scheme. The simulation results show that the proposed scheme effectively removes noise and preserves the main features of multispectral image data by taking channel coupling into consideration.
A dynamic random‐effects model for recovery of skin barrier function: evaluation of the efficacy of different skin care products

Apparently, the use of mathematical and statistical models to describe the structure and function of the skin barrier is rather limited. The skin barrier protects the body against uncontrolled loss of water and desiccation, and prevents environmental substances from entering the skin. A simple measure of the barrier function is the transepidermal water loss (TEWL), which is easy to measure. Healthy skin has low TEWL values, whereas various skin diseases result in high TEWL values and eventually in the development of dry skin. The use of skin care products can protect and prevent dry skin. In this study several different trial formulations are compared with respect to their abilities as skin care products. The study is performed as a longitudinal study on mice, where the skin barrier is broken by means of acetone and then treated with one of the formulations. We analysed the data by means of a semimechanistic random‐effects model with similarities to pharmacokinetic models. In the model each formulation is characterized by two parameters: one that corresponds to the initial barrier restoration effect and one that corresponds to the elimination rate.
Nanoscale imaging of individual amyloid aggregates extracted from brains of Alzheimer and Parkinson patients reveals presence of lipids in α‐synuclein but not in amyloid β1–42 fibrils

Abrupt aggregation of misfolded proteins is the underlying molecular cause of Alzheimer disease (AD) and Parkinson disease (PD). Both AD and PD are severe pathologies that affect millions of people around the world. A small 42 amino acid long peptide, known as amyloid β (Aβ), aggregates in the frontal cortex of AD patients forming oligomers and fibrils, highly toxic protein aggregates that cause progressive neuron death. Similar aggregates of α‐synuclein (α‐Syn), a small protein that facilitates neurotransmitter release, are observed in the midbrain, hypothalamus, and thalamus of people with PD. In this study, we utilized the innovative nano‐Infrared imaging technique to investigate the structural organization of individual Aβ and α‐syn fibrils postmortem extracted from brains of AD and PD patients, respectively. We observed two morphologically different Aβ and α‐Syn fibril polymorphs in each patient's brain. One had twisted topology, whereas another exhibited flat tape‐like morphology. We found that both polymorphs shared the same parallel β‐sheet‐dominated secondary structure. These findings suggested that both fibril polymorphs were built from structurally similar if not identical filaments that coiled forming twisted fibrils or associated side‐by‐side in the case of straight Aβ and α‐Syn fibrils. Nano‐Infrared analysis of individual protein aggregates also revealed the presence of lipids in the structure of both twisted and tape‐like α‐Syn fibrils that were not observed in any of the Aβ fibril polymorphs. These findings demonstrate that lipid membranes can play a critically important role in the onset and progression of PD.
Ultrathin, Soft, Bioresorbable Organic Electrochemical Transistors for Transient Spatiotemporal Mapping of Brain Activity

A critical challenge lies in the development of the next‐generation neural interface, in mechanically tissue‐compatible fashion, that offer accurate, transient recording electrophysiological (EP) information and autonomous degradation after stable operation. Here, an ultrathin, lightweight, soft and multichannel neural interface is presented based on organic‐electrochemical‐transistor‐(OECT)‐based network, with capabilities of continuous high‐fidelity mapping of neural signals and biosafety active degrading after performing functions. Such platform yields a high spatiotemporal resolution of 1.42 ms and 20 µm, with signal‐to‐noise ratio up to ≈37 dB. The implantable OECT arrays can well establish stable functional neural interfaces, designed as fully biodegradable electronic platforms in vivo. Demonstrated applications of such OECT implants include real‐time monitoring of electrical activities from the cortical surface of rats under various conditions (e.g., narcosis, epileptic seizure, and electric stimuli) and electrocorticography mapping from 100 channels. This technology offers general applicability in neural interfaces, with great potential utility in treatment/diagnosis of neurological disorders.
Transition Substitution of Desired Bases in Human Pluripotent Stem Cells with Base Editors: A Step-by-Step Guide

The recent advances in human pluripotent stem cells (hPSCs) enable to precisely edit the desired bases in hPSCs to be used for the establishment of isogenic disease models and autologous ex vivo cell therapy. The knock-in approach based on the homologous directed repair with Cas9 endonuclease, causing DNA double-strand breaks (DSBs), produces not only insertion and deletion (indel) mutations but also deleterious large deletions. On the contrary, due to the lack of Cas9 endonuclease activity, base editors (BEs) such as adenine base editor (ABE) and cytosine base editor (CBE) allow precise base substitution by conjugated deaminase activity, free from DSB formation. Despite the limitation of BEs in transition substitution, precise base editing by BEs with no massive off-targets is suggested to be a prospective alternative in hPSCs for clinical applications. Considering the unique cellular characteristics of hPSCs, a few points should be considered. Herein, we describe an updated and optimized protocol for base editing in hPSCs. We also describe an improved methodology for CBE-based C to T substitutions, which are generally lower than A to G substitutions in hPSCs.
Redox phase transformations in magnetite nanoparticles: impact on their composition, structure and biomedical applications

Magnetite nanoparticles (NPs) are one of the most investigated nanomaterials so far and modern synthesis methods currently provide an exceptional control of their size, shape, crystallinity and surface functionalization. These advances have enabled their use in different fields ranging from environmental applications to biomedicine. However, several studies have shown that the precise composition and crystal structure of magnetite NPs depend on their redox phase transformations, which have a profound impact on their physicochemical properties and, ultimately, on their technological applications. Although the physical mechanisms behind such chemical transformations in bulk materials have been known for a long time, experiments on NPs with large surface-to-volume ratios have revealed intriguing results. This article is focused on reviewing the current status of the field. Following an introduction on the fundamental properties of magnetite and other related iron oxides (including maghemite and wüstite), some basic concepts on the chemical routes to prepare iron oxide nanomaterials are presented. The key experimental techniques available to study phase transformations in iron oxides, their advantages and drawbacks to the study of nanomaterials are then discussed. The major section of this work is devoted to the topotactic oxidation of magnetite NPs and, in this regard, the cation diffusion model that accounts for the experimental results on the kinetics of the process is critically examined. Since many synthesis routes rely on the formation of monodisperse magnetite NPs via oxidation of wüstite counterparts, the modulation of their physical properties by crystal defects arising from the oxidation process is also described. Finally, the importance of a precise control of the composition and structure of magnetite-based NPs is discussed and its role in their biomedical applications is highlighted.
Analogies of phonon anomalies and electronic gap features in the infrared response of Sr 14−x Ca x Cu24O41 and underdoped YBa2Cu3O 6+x

We present an experimental and theoretical study which compares the phonon anomalies and the electronic gap features in the infrared response of the weakly coupled two-leg-ladders in Sr 14−x Ca x Cu24O41 (SCCO) with those of the underdoped high-T c superconductor YBa2Cu3O 6+x (YBCO) and thereby reveals some surprising analogies. Specifically, we present a phenomenological model that describes the anomalous doping- and temperature-dependence of some of the phonon features in the a-axis response (field along the rungs of the ladders) of SCCO. It assumes that the phonons are coupled to charge oscillations within the ladders. Their changes with decreasing temperature reveal the formation of a crystal (density wave) of hole pairs that are oriented along the rungs. We also discuss the analogy to a similar model that was previously used to explain the phonon anomalies and an electronic plasma mode in the c-axis response (field perpendicular to the CuO2 planes) of YBCO. We further confirm that an insulator-like pseudogap develops in the a-axis conductivity of SCCO which closely resembles that in the c-axis conductivity of YBCO. Most surprisingly, we find that the c-axis conductivity (field along the legs of the ladders) of SCCO is strikingly similar to the in-plane one (field parallel to the CuO2 planes) of YBCO. Notably, in both cases a dip feature develops in the normal state spectra that is connected with a spectral weight shift toward low frequencies and can thus be associated with precursor superconducting pairing correlations that are lacking macroscopic phase coherence. This SCCO–YBCO analogy indicates that collective degrees of freedom contribute to the low-energy response of underdoped high T c cuprates and it even suggests that the charges in the CuO2 planes tend to segregate forming quasi-one-dimensional structures similar to the two-leg ladders, as predicted for the stripe-scenario or certain intertwinned states.
Decoding fMRI alcohol cue reactivity and its association with drinking behaviour

Background Cue reactivity, the enhanced sensitivity to conditioned cues, is associated with habitual and compulsive alcohol consumption. However, most previous studies in alcohol use disorder (AUD) compared brain activity between alcohol and neutral conditions, solely as cue-triggered neural reactivity. Objective This study aims to find the neural subprocesses during the processing of visual alcohol cues in AUD individuals, and how these neural patterns are predictive for relapse. Methods Using cue reactivity and rating tasks, we separately modelled the patterns decoding the processes of visual object recognition and reward appraisal of alcohol cues with representational similarity analysis, and compared the decoding involvements (ie, distance between neural responses and hypothesised decoding models) between AUD and healthy individuals. We further explored connectivity between the identified neural systems and the whole brain and predicted relapse within 6 months using decoding involvements of the neural patterns. Findings AUD individuals, compared with healthy individuals, showed higher involvement of motor-related brain regions in decoding visual features, and their reward, habit and executive networks were more engaged in appraising reward values. Connectivity analyses showed the involved neural systems were widely connected with higher cognitive networks during alcohol cue processing in AUD individuals, and decoding involvements of frontal eye fields and dorsolateral prefrontal cortex could contribute to relapse prediction. Conclusions These findings provide insight into how AUD individuals differently decode alcohol cues compared with healthy participants, from the componential processes of visual object recognition and reward appraisal. Clinical implications The identified patterns are suggested as biomarkers and potential therapeutic targets in AUD.