Miracle-dz/UniFAR-FTUs huggingface dataset:
A Randomized Controlled Trial Investigating the Feasibility of a Low-Intensity Psychological Intervention for Fear of Memory Loss and Quality of Life in Older Adults: Protocol for the Reducing Fear and Avoidance of Memory Loss (REFRAME) Study

Background Dementia is the most feared disease associated with aging. Prolonged fears about memory loss and dementia can have harmful consequences even in the absence of cognitive decline. Fear of dementia is associated with poorer health outcomes and psychological well-being and increased memory failures in older adults. Objective We will conduct a randomized controlled trial to determine the feasibility of a tailored, web-based mindfulness program to reduce fear of memory loss and increase quality of life in older adults experiencing heightened fear. Methods Eighty participants will be recruited and divided into 2 groups (40 in each group). One group will receive psychoeducation plus mindfulness training. A second group will receive psychoeducation, mindfulness training, and additional modules targeting maladaptive behavioral avoidance (ie, social and cognitive withdrawal). Results Our recent etiological model posits that maladaptive behavioral avoidance strategies critically underlie psychosocial dysfunction associated with fear of memory loss. Thus, we predict better outcomes in the second group, including reduced fear of memory loss (primary outcome), Alzheimer disease, anxiety, and subjective memory failures, and increased quality of life (secondary outcomes). Outcome measures will be applied at 5 time points (before, baseline, interim, and after the intervention, and at 3-month follow-up). Data will be analyzed using mixed models and correlations. Conclusions Results from this study will contribute to the current literature on dementia-related fear and improve our understanding of how to effectively address and reduce these fears. Trial Registration ClinicalTrials.gov NCT04821960; https://clinicaltrials.gov/ct2/show/NCT04821960. International Registered Report Identifier (IRRID) PRR1-10.2196/30514
From Receptive to Perceptive Fields: Size-Dependent Asymmetries in Both Negative Afterimages and Subcortical On and Off Post-Stimulus Responses

Negative afterimages are perceptual phenomena that occur after physical stimuli disappear from sight. Their origin is linked to transient post-stimulus responses of visual neurons. The receptive fields (RFs) of these subcortical ON- and OFF-center neurons exhibit antagonistic interactions between central and surrounding visual space, resulting in selectivity for stimulus polarity and size. These two features are closely intertwined, yet their relationship to negative afterimage perception remains unknown. Here we tested whether size differentially affects the perception of bright and dark negative afterimages in humans of both sexes, and how this correlates with neural mechanisms in subcortical ON and OFF cells. Psychophysically, we found a size-dependent asymmetry whereby dark disks produce stronger and longer-lasting negative afterimages than bright disks of equal contrast at sizes >0.8°. Neurophysiological recordings from retinal and relay cells in female cat dorsal lateral geniculate nucleus showed that subcortical ON cells exhibited stronger sustained post-stimulus responses to dark disks, than OFF cells to bright disks, at sizes >1°. These sizes agree with the emergence of center-surround antagonism, revealing stronger suppression to opposite-polarity stimuli for OFF versus ON cells, particularly in dorsal lateral geniculate nucleus. Using a network-based retino-geniculate model, we confirmed stronger antagonism and temporal transience for OFF-cell post-stimulus rebound responses. A V1 population model demonstrated that both strength and duration asymmetries can be propagated to downstream cortical areas. Our results demonstrate how size-dependent antagonism impacts both the neuronal post-stimulus response and the resulting afterimage percepts, thereby supporting the idea of perceptual RFs reflecting the underlying neuronal RF organization of single cells. SIGNIFICANCE STATEMENT Visual illusions occur when sensory inputs and perceptual outcomes do not match, and provide a valuable tool to understand transformations from neural to perceptual responses. A classic example are negative afterimages that remain visible after a stimulus is removed from view. Such perceptions are linked to responses in early visual neurons, yet the details remain poorly understood. Combining human psychophysics, neurophysiological recordings in cats and retino-thalamo-cortical computational modeling, our study reveals how stimulus size and the receptive-field structure of subcortical ON and OFF cells contributes to the parallel asymmetries between neural and perceptual responses to bright versus dark afterimages. Thus, this work provides a deeper link from the underlying neural mechanisms to the resultant perceptual outcomes.
Reciprocal regulation of spontaneous synaptic vesicle fusion by Fragile X mental retardation protein and group I metabotropic glutamate receptors

Fragile X mental retardation protein (FMRP) is a neuronal protein mediating multiple functions, with its absence resulting in one of the most common monogenic causes of autism, Fragile X syndrome (FXS). Analyses of FXS pathophysiology have identified a range of aberrations in synaptic signaling pathways and plasticity associated with group I metabotropic glutamate (mGlu) receptors. These studies, however, have mostly focused on the post‐synaptic functions of FMRP and mGlu receptor activation, and relatively little is known about their presynaptic effects. Neurotransmitter release is mediated via multiple forms of synaptic vesicle (SV) fusion, each of which contributes to specific neuronal functions. The impacts of mGlu receptor activation and loss of FMRP on these SV fusion events remain unexplored. Here we combined electrophysiological and fluorescence imaging analyses on primary hippocampal cultures prepared from an Fmr1 knockout (KO) rat model. Compared to wild‐type (WT) hippocampal neurons, KO neurons displayed an increase in the frequency of spontaneous excitatory post‐synaptic currents (sEPSCs), as well as spontaneous SV fusion events. Pharmacological activation of mGlu receptors in WT neurons caused a similar increase in spontaneous SV fusion and sEPSC frequency. Notably, this increase in SV fusion was not observed when spontaneous activity was blocked using the sodium channel antagonist tetrodotoxin. Importantly, the effect of mGlu receptor activation on spontaneous SV fusion was occluded in Fmr1 KO neurons. Together, our results reveal that FMRP represses spontaneous presynaptic SV fusion, whereas mGlu receptor activation increases this event. This reciprocal control appears to be mediated via their regulation of intrinsic neuronal excitability.
Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension

Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.
Early Responses to Low-Dose Ionizing Radiation in Cellular Lens Epithelial Models

Cataract is the leading cause of visual impairment which can result in blindness. Cataract formation has been associated with radiation exposure; however, the mechanistic understanding of this phenomenon is still lacking. The goal of this study was to investigate mechanisms of cataract induction in isolated lens epithelial cells (LEC) exposed to ionizing radiation. Human LECs from different genetic backgrounds (SV40 immortalized HLE-B3 and primary HLEC cells) were exposed to varying doses of 137Cs gamma rays (0, 0.1, 0.25 and 0.5 Gy), at low (0.065 Gy/min) and higher (0.3 Gy/min) dose rates. Different assays were used to measure LEC response for, e.g., viability, oxidative stress, DNA damage studies, senescence and changes to telomere length/telomerase activity at two time points (1 h and 24 h, or 24 h and 15 days, depending on the type of assay and expected response time). The viability of cells decreased in a dose-dependent manner within 24 h of irradiation. Measurement of reactive oxygen species showed an increase at 1 h postirradiation, which was alleviated within 24 h. This was consistent with DNA damage results showing high DNA damage after 1 h postirradiation which reduced significantly (but not completely) within 24 h. Induction of senescence was also observed 15 days postirradiation, but this was not attributed to telomere erosion or telomerase activity reduction. Overall, these findings provide a mechanistic understanding of low-dose radiation-induced cataractogenesis which will ultimately help to inform judgements on the magnitude of risk and improve existing radiation protection procedures.
Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel

Significance The heart autoregulates its contractile strength to maintain cardiac output when pumping blood against the mechanical afterload from vascular resistance. Increased afterload in cardiovascular diseases is associated with cardiac arrhythmias. However, the underlying mechanisms remain elusive. Here, we studied the afterload effect on electrophysiology by embedding single cardiomyocytes in a three-dimensional viscoelastic hydrogel to apply afterload during cell contraction. We found that afterload is acutely transduced via nitric oxide synthase 1 (NOS1) signaling to modulate multiple ion channels to prolong action potential, increase Ca2+ transient, and enhance contractility. However, higher afterload causes a discordant alternans that is arrhythmogenic. Hence, our findings reveal an afterload-induced mechano-chemo-electro-transduction pathway that closes feedback loops in cardiac excitation–contraction coupling to enable autoregulation of contractility. The heart pumps blood against the mechanical afterload from arterial resistance, and increased afterload may alter cardiac electrophysiology and contribute to life-threatening arrhythmias. However, the cellular and molecular mechanisms underlying mechanoelectric coupling in cardiomyocytes remain unclear. We developed an innovative patch-clamp-in-gel technology to embed cardiomyocytes in a three-dimensional (3D) viscoelastic hydrogel that imposes an afterload during regular myocyte contraction. Here, we investigated how afterload affects action potentials, ionic currents, intracellular Ca2+ transients, and cell contraction of adult rabbit ventricular cardiomyocytes. We found that afterload prolonged action potential duration (APD), increased transient outward K+ current, decreased inward rectifier K+ current, and increased L-type Ca2+ current. Increased Ca2+ entry caused enhanced Ca2+ transients and contractility. Moreover, elevated afterload led to discordant alternans in APD and Ca2+ transient. Ca2+ alternans persisted under action potential clamp, indicating that the alternans was Ca2+ dependent. Furthermore, all these afterload effects were significantly attenuated by inhibiting nitric oxide synthase 1 (NOS1). Taken together, our data reveal a mechano-chemo-electrotransduction (MCET) mechanism that acutely transduces afterload through NOS1–nitric oxide signaling to modulate the action potential, Ca2+ transient, and contractility. The MCET pathway provides a feedback loop in excitation–Ca2+ signaling–contraction coupling, enabling autoregulation of contractility in cardiomyocytes in response to afterload. This MCET mechanism is integral to the individual cardiomyocyte (and thus the heart) to intrinsically enhance its contractility in response to the load against which it has to do work. While this MCET is largely compensatory for physiological load changes, it may also increase susceptibility to arrhythmias under excessive pathological loading.
Chloroform extract of Calliandra portoricensis inhibits tumourigenic effect of N-methyl-N-nitrosourea and benzo(a)pyrene in breast experimental cancer

Abstract Calliandra portoricensis (C. portoricensis) is used in herbal homes in Nigeria to manage breast diseases. We investigated the anti-tumourigenic effects of chloroform extract of C. portoricensis (CP) in breast experimental cancer induced by N-methyl-N-nitrosourea (NMU) and benzo-(a)-pyrene (BaP). Fifty-six female rats were assigned into seven equal groups: Group 1 served as control, group 2 received NMU and BaP (50 mg/kg, each), groups 3 and 4 received [NMU + BaP] and treated with CP at 50 and 100 mg/kg, respectively. Group 5 received CP (100 mg/kg), group 6 received [NMU + BaP] and vincristine (0.5 mg/kg), while group 7 received vincristine (0.5 mg/kg). The NMU and BaP (i.p) were dissolved in normal saline and corn oil, respectively. The CP (oral) and vincristine (i.p) were given thrice and twice per week, respectively for 10 weeks. The [NMU + BaP] intoxication significantly decreased body weight gain by 32% while organo-somatic weight of mammary gland increased by 37%. Also, [NMU + BaP] decreased the activities of mammary catalase, glutathione-s-transferase, glutathione peroxidase, superoxide dismutase and total sulphurhydryl by 34%, 31%, 35%, 35% and 33%, respectively. The [NMU + BaP] increased inflammatory and oxidative stress markers; nitrite, lipid peroxidation and myeloperoxidase by 62%, 57% and 361%, respectively. Strong expression of BCL-2, IL-6, COX 2, β-catenin and iNOS in [NMU + BaP]-administered rats were observed. Histology revealed glands with malignant epithelial cells and high nucleocytoplasm in [NMU + BaP] rats. Treatment with CP attenuated inflammation, apoptosis and restored cyto-architecture of mammary gland. Overall, CP abates mammary tumourigenesis by targeting cellular pathways of inflammation and apoptosis.
Experimental determination of wettability and heterogeneity effect on CO 2 distribution in porous media

: The geological sequestration of carbon dioxide (CO 2 ) is considered a promising technology for CO 2 emissions. However, accurate estimation of the storage capacity for CO 2 remains a challenge owing to the effect of capillary pressure variation. The CO 2 ‐salty aqueous contact angle and sub‐core scale heterogeneity are the major factors that influence capillary pressure. This paper reports the results of CO 2 /brine two‐phase flow experiments in porous media by using an X‐ray computed tomography (CT) technique at 40°C and 8 Mpa and examines the strong influence of wettability and sub‐core scale heterogeneities on the spatial distribution of CO 2 . Gas injection experiments were conducted at flow rates of 0.1 mL/min, 0.2 mL/min, and 0.5 mL/min, and the porous media were packed with feldspar, quartz, or dolomite. This study indicates that at the core scale, the wettability of porous media is a crucial factor in determining CO 2 saturation. Capillary fingering and low CO 2 saturation occurred with high water wettability. Sub‐core scale heterogeneities controlled the CO 2 distribution and saturation variation along the porous media, particular that with small pore sizes. © 2015 Society of Chemical Industry and John Wiley & Sons, Ltd
Outer membrane permeability: Antimicrobials and diverse nutrients bypass porins in Pseudomonas aeruginosa

Significance Novel antibiotics are urgently needed to resolve the current antimicrobial resistance crisis. For critical pathogens, drug entry through the cell envelope is one of the major challenges in the development of effective novel antibiotics. Envelope proteins forming water-filled channels, so-called porins, are commonly thought to be essential for entry of hydrophilic molecules, but we show here for the critical pathogen Pseudomonas aeruginosa that almost all antibiotics and diverse hydrophilic nutrients bypass porins and instead permeate directly through the outer membrane lipid bilayer. However, carboxylate groups hinder bilayer penetration, and Pseudomonas thus needs porins for efficient utilization of carboxylate-containing nutrients such as succinate. The major porin-independent entry route might open opportunities for facilitating drug delivery into bacteria. Gram-negative bacterial pathogens have an outer membrane that restricts entry of molecules into the cell. Water-filled protein channels in the outer membrane, so-called porins, facilitate nutrient uptake and are thought to enable antibiotic entry. Here, we determined the role of porins in a major pathogen, Pseudomonas aeruginosa, by constructing a strain lacking all 40 identifiable porins and 15 strains carrying only a single unique type of porin and characterizing these strains with NMR metabolomics and antimicrobial susceptibility assays. In contrast to common assumptions, all porins were dispensable for Pseudomonas growth in rich medium and consumption of diverse hydrophilic nutrients. However, preferred nutrients with two or more carboxylate groups such as succinate and citrate permeated poorly in the absence of porins. Porins provided efficient translocation pathways for these nutrients with broad and overlapping substrate selectivity while efficiently excluding all tested antibiotics except carbapenems, which partially entered through OprD. Porin-independent permeation of antibiotics through the outer-membrane lipid bilayer was hampered by carboxylate groups, consistent with our nutrient data. Together, these results challenge common assumptions about the role of porins by demonstrating porin-independent permeation of the outer-membrane lipid bilayer as a major pathway for nutrient and drug entry into the bacterial cell.
Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

Abstract Carbonic anhydrases (CAs, EC 4.2.1.1) are enzymes involved in a multitude of diseases, and their inhibitors are in clinical use as drugs for the management of glaucoma, epilepsy, obesity, and tumours. In the last decade, multitargeting approaches have been proposed by hybridisation of CA inhibitors (CAIs) of sulphonamide, coumarin, and sulphocoumarin types with NO donors, CO donors, prostaglandin analogs, β-adrenergic blockers, non-steroidal anti-inflammatory drugs, and a variety of anticancer agents (cytotoxic drugs, kinase/telomerase inhibitors, P-gp and thioredoxin inhibitors). Many of the obtained hybrids showed enhanced efficacy compared to the parent drugs, making multitargeting an effective and innovative approach for various pharmacological applications.
Gold Dimer Nanoantenna with Slanted Gap for Tunable LSPR and Improved SERS

We focus on improving the surface-enhanced Raman scattering (SERS) of dimer nanoantenna by tailoring the shape of the coupled nanoantennas extremities from rounded to straight or slanted ones. A numerical model based on the discrete dipole approximation method—taking into account periodicity, adhesion layer, and roughness—is first validated by comparison with localized surface plasmon resonance (LSPR) and SERS experiments on round-edged dimer nanoantennas and then used to investigate the effect of the straight or slanted gap in the dimer antenna. Simulations show that both LSPR and SERS can be tuned by changing the gap slanting angle. The SERS enhancement factor can also be improved by 2 orders of magnitude compared to the one reached using a rounded gap. Therefore, the slanting angle can be used as a new control parameter in the design of SERS substrates to guarantee stronger field confinement and higher sensitivity, especially as its feasibility is demonstrated.
Pain-coping types among older community-dwelling care receivers with chronic pain

Abstract Objectives There is a lack of knowledge on coping with pain and sub-group specific pain-coping profiles among older home care receivers with chronic pain. To describe pain-coping strategies, identify subgroups based on cognitive and behavioral pain-coping strategies and pain-related psychological impairment and to compare these groups with regard to socio-demographic, medical, pharmacological and psychological characteristics. Method Data of 212 care receivers were examined using the German pain-coping questionnaire (FESV) to determine how they cope with pain. Subgroups were identified using hierarchic agglomerative cluster analysis, using Ward’s algorithm and squared Euclidean distance, and characterized using socio-demographic, medical, pharmacological and psychological parameters. Multinomial logistic regression was used to identify variables associated with the subgroups. Results Older care receivers apply cognitive and behavioral strategies to manage pain. Three subgroups were identified: Cluster 1 (25.9%) with good coping competences and little psychological impairment, Cluster 2 (40.1%) with poor coping competences and high psychological impairment, and Cluster 3 (34%) with good coping competences and high psychological impairment. Significant differences between the clusters were observed for age, pain intensity, pain-related interference, daily activities, depression and resilience. Logistic regression demonstrated that belonging to Cluster 2 was associated with the number of pain-reducing medications, depression and resilience. Belonging to Cluster 3 was significantly linked to daily activities, the number of pain medications, depression and the level of care required. Conclusion Differentiating between pain-coping profiles in the group of older care receivers with chronic pain necessitates target group-specific pain-oriented psychotherapeutic interventions, which can result in improved pain management.
Functionalized Nanoporous Thin Films and Fibers from Photocleavable Block Copolymers Featuring Activated Esters

A series of poly(pentafluorophenyl (methyl)acrylates)-block-poly(ethylene oxide) with o-nitrobenzyl ester photocleavable junctions (PPFP(M)A-hv-PEO) were synthesized by RAFT polymerization. The block copolymers were used to fabricate thin films and fibers by spin-coating and electrospinning, respectively. After solvent annealing, UV exposure, and washing with methanol/water to remove the minor PEO block, nanoporous structures were obtained. Both the porous thin films and fibers remained reactive to amine substitution of the pentafluorophenyl esters under mild conditions, which was confirmed by XPS, fluorescence confocal microscopy, FT-IR, and contact angle measurements.