Miracle-dz/UniFAR-FTUs huggingface dataset:
Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common (60% to 80%) age‐related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aβ, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells’ life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.
Sub-epidermal Expression of ENHANCER OF TRIPTYCHON AND CAPRICE1 and Its Role in Root Hair Formation Upon Pi Starvation

Root hair patterning is best studied in Arabidopsis thaliana. A pattern of root hair and non-root hair files is governed by a gene-regulatory network of activators and inhibitors. Under phosphate starvation conditions, extra root hairs are formed in non-root hair positions. This raises the question, whether and how this environmental stimulus is mediated by the known root hair gene network. In this study, we provide genetic and molecular data on the role of ETC1 in the phosphate starvation induced ectopic root hair formation. We show that the expression in the epidermis is irregular and reduced and that a new expression domain is induced in the sub-epidermis. By expressing ETC1 in the sub-epidermis, we show that this is sufficient to induce extra root hair formation in N-files. This suggests that the phosphate induced expressional switch from epidermal to epidermal plus sub-epidermal expression of ETC1 is one environmental input to the underlying patterning network.
Characterization of retinal regeneration in adult zebrafish following multiple rounds of phototoxic lesion

Müller glia in the zebrafish retina respond to retinal damage by re-entering the cell cycle, which generates large numbers of retinal progenitors that ultimately replace the lost neurons. In this study we compared the regenerative outcomes of adult zebrafish exposed to one round of phototoxic treatment with adult zebrafish exposed to six consecutive rounds of phototoxic treatment. We observed that Müller glia continued to re-enter the cell cycle to produce clusters of retinal progenitors in zebrafish exposed to multiple rounds of phototoxic light. Some abnormalities were noted, however. First, we found that retinas exposed to multiple rounds of damage exhibited a greater loss of photoreceptors at 36 hours of light damage than retinas that were exposed to their first round of light damage. In addition, we found that Müller glia appeared to have an increase in the acute gliotic response in retinas exposed to multiple rounds of light treatment. This was evidenced by cellular hypertrophy, changes in GFAP cellular localization, and transient increases in stat3 and gfap expression. Finally, following the sixth round of phototoxic lesion, we observed a significant increase in mis-localized HuC/D-positive amacrine and ganglion cells in the inner plexiform layer and outer retina, and a decreased number of regenerated blue cone photoreceptors. These data add to recent findings that retinal regeneration in adult zebrafish occurs concomitant with Müller glia reactivity and can result in the generation of aberrant neurons. These data are also the first to demonstrate that Müller glia appear to modify their phenotype in response to multiple rounds of phototoxic lesion, exhibiting an increase in acute gliosis while maintaining a remarkable capacity for long-term regeneration of photoreceptors.
The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity

Sudden unexpected cardiac death (SCD) accounts for up to half of all-cause mortality of heart failure patients. Standardized cardiology tools such as electrocardiography, cardiac imaging, electrophysiological and serum biomarkers cannot accurately predict which patients are at risk of life-threatening arrhythmic episodes. Recently, a common variant of the histidine-rich calcium binding protein (HRC), the Ser96Ala, was identified as a potent biomarker of malignant arrhythmia triggering in these patients. HRC has been shown to be involved in the regulation of cardiac sarcoplasmic reticulum (SR) Ca2+ cycling, by binding and storing Ca2+ in the SR, as well as interacting with the SR Ca2+ uptake and release complexes. The underlying mechanisms, elucidated by studies at the molecular, biochemical, cellular and intact animal levels, indicate that transversion of Ser96 to Ala results in abolishment of an HRC phosphorylation site by Fam20C kinase and dysregulation of SR Ca2+ cycling. This is mediated through aberrant SR Ca2+ release by the ryanodine receptor (RyR2) quaternary complex, due to the impaired HRC/triadin interaction, and depressed SR Ca2+ uptake by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, due to the impaired HRC/SERCA2 interaction. Pharmacological intervention with KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), in the HRC Ser96Ala mouse model, reduced the occurrence of malignant cardiac arrhythmias. Herein, we summarize the current evidence on the pivotal role of HRC in the regulation of cardiac rhythmicity and the importance of HRC Ser96Ala as a genetic modifier for arrhythmias in the setting of heart failure.
Amphiphilic block copolymers in drug delivery: advances in formulation structure and performance

ABSTRACT Introduction: Nanostructured delivery vehicles can address key challenges facing drug delivery, including the lipophilic nature of therapeutic compounds and their effective transport through the body. Amphiphilic block copolymers that self-assemble offer advantages compared with homopolymer-, lipid-, and protein-based delivery vehicles. Poly(ethylene oxide)-poly(propylene oxide) amphiphilic block copolymers (Poloxamers) serve well as pharmaceutical excipients because of their highly tunable association properties, low toxicity, and ability to functionalize. The formulation nanostructure underpins performance across various administration routes and diseases, but is strongly dependent on the amphiphile, drug, and environment (temperature, concentration, and types of additives), thus demanding further elucidation. Areas covered: The phase behavior of Poloxamers in aqueous solution is presented first, to inform an overview of drug encapsulation processes. The formulation composition and preparation method are centrally important to the nanostructure obtained. Several self-assembled structures are discussed which present advantages for particular administration routes: transdermal, ophthalmic, oral, nasal, and subcutaneous. Many diseases are treatable through these routes, e.g., inflammation, diabetes, hypertension, and cancer. Expert opinion: The exceptional ability to tune amphiphilic block copolymer nanostructure (micelles, hydrogels, lyotropic liquid crystals, etc.) renders them a powerful tool in the formulation of drug delivery systems, offering multiple processing options and physical states to accommodate diverse drugs and administration pathways.
Compressive force induces reversible chromatin condensation and cell geometry–dependent transcriptional response

Fibroblasts exhibit heterogeneous cell geometries in tissues and integrate both mechanical and biochemical signals in their local microenvironment to regulate genomic programs via chromatin remodelling. While in connective tissues fibroblasts experience tensile and compressive forces (CFs), the role of compressive forces in regulating cell behavior and, in particular, the impact of cell geometry in modulating transcriptional response to such extrinsic mechanical forces is unclear. Here we show that CF on geometrically well-defined mouse fibroblast cells reduces actomyosin contractility and shuttles histone deacetylase 3 (HDAC3) into the nucleus. HDAC3 then triggers an increase in the heterochromatin content by initiating removal of acetylation marks on the histone tails. This suggests that, in response to CF, fibroblasts condense their chromatin and enter into a transcriptionally less active and quiescent states as also revealed by transcriptome analysis. On removal of CF, the alteration in chromatin condensation was reversed. We also present a quantitative model linking CF-dependent changes in actomyosin contractility leading to chromatin condensation. Further, transcriptome analysis also revealed that the transcriptional response of cells to CF was geometry dependent. Collectively, our results suggest that CFs induce chromatin condensation and geometry-dependent differential transcriptional response in fibroblasts that allows maintenance of tissue homeostasis.
Evaluation of Differentiated Bone Cells Proliferation by Blue Shark Skin Collagen via Biochemical for Bone Tissue Engineering

Collagen from a marine resource is believed to have more potential activity in bone tissue engineering and their bioactivity depends on biochemical and structural properties. Considering the above concept, pepsin soluble collagen (PSC) and acid soluble collagen (ASC) from blue shark (Prionace glauca) skin were extracted and its biochemical and osteogenic properties were investigated. The hydroxyproline content was higher in PSC than ASC and the purified collagens contained three distinct bands α1, α2, and β dimer. The purity of collagen was confirmed by the RP-HPLC profile and the thermogravimetric data showed a two-step thermal degradation pattern. ASC had a sharp decline in viscosity at 20–30 °C. Scanning electron microscope (SEM) images revealed the fibrillar network structure of collagens. Proliferation rates of the differentiated mouse bone marrow-mesenchymal stem (dMBMS) and differentiated osteoblastic (dMC3T3E1) cells were increased in collagen treated groups rather than the controls and the effect was dose-dependent, which was further supported by higher osteogenic protein and mRNA expression in collagen treated bone cells. Among two collagens, PSC had significantly increased dMBMS cell proliferation and this was materialized through increasing RUNX2 and collagen-I expression in bone cells. Accordingly, the collagens from blue shark skin with excellent biochemical and osteogenic properties could be a suitable biomaterial for therapeutic application.
Early Growth Hormone Intervention Improves Glucose Metabolism in Adult Rats Born Small for Gestational Age.

BACKGROUND Small for gestational age (SGA) due to intrauterine malnourishment is closely related to metabolic syndrome and type 2 diabetes mellitus. Growth Hormone (GH) treatment has been demonstrated to influence metabolic parameters and islet function of SGA individuals. The present study demonstrates the effects of early GH treatment on glucose tolerance and expression of pancreatic duodenal homeobox 1 (Pdx1) of SGA rats during adulthood METHODS: SGA rat model was induced by restricting food intake during pregnancy. GH or normal saline was administered during postnatal days 21-35 of SGA rats and appropriate for gestational age (AGA) rats, respectively. RESULTS In early adulthood (postnatal day 70), as compared to AGA rats, SGA rats showed: (1) decreased body weight; (2) increased postprandial blood glucose; and (3) down-regulated Pdx1 with increased histone deacetylase (HDAC) and down-regulated histone H3-lysine 4 methyltransferase SET7/9. Exogenous GH administration led to a restoration of body weight and normalized glucose tolerance due to an enhanced Pdx1 expression, accompanied by decreased HDAC and up-regulated SET7/9 in SGA rats in early adulthood. CONCLUSION Our results demonstrate positive effects on glucose metabolism by an early and short GH treatment in SGA adulthood.
Fast Dynamic in vivo Monitoring of Erk Activity at Single Cell Resolution in DREKA Zebrafish

Precise regulation of signaling pathways in single cells underlies tissue development, maintenance and repair in multicellular organisms, but our ability to monitor signaling dynamics in living vertebrates is currently limited. We implemented kinase translocation reporter (KTR) technology to create DREKA (“dynamic reporter of Erk activity”) zebrafish, which allow one to observe Erk activity in vivo at single cell level with high temporal resolution. DREKA zebrafish faithfully reported Erk activity after muscle cell wounding and revealed the kinetics of small compound uptake. Our results promise that kinase translocation reporters can be adapted for further applications in developmental biology, disease modeling, and in vivo pharmacology in zebrafish.
Leptin Selectively Regulates Nutrients Metabolism in Nile Tilapia Fed on High Carbohydrate or High Fat Diet

Leptin is known to inhibit appetite and promote energy metabolism in vertebrates. Leptin resistance (LR) commonly occurs in diet-induced obesity (DIO) in mammals. However, the roles of leptin in the energy homeostasis in DIO animals with LR remain unclear. Here we first verified the high expression of leptin in subcutaneous adipose tissue (SCAT) as in liver in Nile tilapia. Furthermore, we produced two types of DIO Nile tilapia by using a high-carbohydrate diet (HCD) or a high-fat diet (HFD), and confirmed the existence of LR in both models. Notably, we found that HCD-DIO fish retained leptin action in the activation of lipid metabolism and showed LR in glucose metabolism regulation, while this selective leptin action between lipid and glucose metabolism was reversed in HFD-DIO fish. Fasting the fish for 1 week completely recovered leptin actions in the regulation of lipid and glucose metabolism. Therefore, leptin may retain more of its activities in animals with LR than previously believed. Evolutionally, this selective regulation of leptin in nutrients metabolism could be an adaptive mechanism in animals to store surplus calories when different types of food are abundant.
The Ecology of Collective Behavior in Ants.

Nest choice in Temnothorax spp. ; task allocation and the regulation of activity in Pheidole dentata, Pogonomyrmex barbatus, and Atta spp. ; and trail networks in Monomorium pharaonis and Cephalotes goniodontus all provide examples of correspondences between the dynamics of the environment and the dynamics of collective behavior. Some important aspects of the dynamics of the environment include stability, the threat of rupture or disturbance, the ratio of inflow and outflow of resources or energy, and the distribution of resources. These correspond to the dynamics of collective behavior, including the extent of amplification, how feedback instigates and inhibits activity, and the extent to which the interactions that provide the information to regulate behavior are local or spatially centralized.
Angelman syndrome–associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome

Deregulation of the HECT ubiquitin ligase UBE3A/E6AP has been implicated in Angelman syndrome as well as autism spectrum disorders. We and others have previously identified the 26S proteasome as one of the major UBE3A-interacting protein complexes. Here, we characterize the interaction of UBE3A and the proteasomal subunit PSMD4 (Rpn10/S5a). We map the interaction to the highly conserved Zn2+-binding N-terminal (AZUL) domain of UBE3A, the integrity of which is crucial for binding to PSMD4. Interestingly, two Angelman syndrome point mutations that affect the AZUL domain show an impaired ability to bind PSMD4. Although not affecting the ubiquitin ligase or the estrogen receptor α–mediated transcriptional regulation activities, these AZUL domain mutations prevent UBE3A from stimulating the Wnt/β-catenin signaling pathway. Taken together, our data indicate that impaired binding to the 26S proteasome and consequential deregulation of Wnt/β-catenin signaling might contribute to the functional defect of these mutants in Angelman syndrome.
The association between paracetamol use and the risk of asthma, rhinitis and eczema in the Polish population.

INTRODUCTION A growing number of epidemiological studies suggest that paracetamol, which is commonly used in children, may be a risk factor for asthma, allergic rhinitis, and atopic eczema. OBJECTIVE The aim of this study was to determine and characterize the correlation between paracetamol use and asthma, allergic rhinitis, and atopic eczema symptoms in the Polish population. MATERIAL AND METHODS The study is part of the ECAP project involving the use of the ISAAC and ECRHS questionnaires. Completed questionnaires of 18,617 subjects, including 10,011 (53.8%) females, were analyzed. Children aged 6-7 (n=4,510), adolescents aged 13-14 (n=4,721), and adults aged 20-44 (n=9,386) constituted 24.2%, 25.4%, and 50.4% of respondents, respectively. Study subjects lived in 8 major urban centres and one rural area. The frequency of paracetamol use during the previous 12 months and symptoms of asthma, allergic rhinitis, and atopic eczema during that period were analyzed. RESULTS The use of paracetamol was associated with a significant dose-dependent increase in the risk of asthma symptoms in all evaluated age groups. This was demonstrated via odds ratios (OR) for developing asthma symptoms, including wheezing or whistling in the chest in 6-7-year-olds and exercise-induced shortness of breath in 13-14-year-olds and adults, depending on the frequency of paracetamol use in the previous 12 months, compared to no paracetamol intake during that period. CONCLUSIONS The use of paracetamol in the last 12 months was associated with a significant dose-dependent increase in the risk of rhinitis and skin allergy symptoms, as demonstrated by the odds ratio. Therefore, frequent paracetamol use may be a risk factor for symptoms of asthma, rhinitis, and skin allergy in the Polish population.
Inflammation-based prognostic scores predict the prognosis of locally advanced cervical esophageal squamous cell carcinoma patients receiving curative concurrent chemoradiotherapy: a propensity score-matched analysis

Introduction The present study investigated the crucial role of inflammation-based prognostic scores in locally advanced cervical esophageal squamous cell carcinoma (ESCC) patients who underwent curative concurrent chemoradiotherapy (CCRT). Methods There were 411 ESCC patients enrolled, including 63 cervical ESCC patients. Using the propensity score matching method, 63 thoracic ESCC patients were matched to the 63 cervical ESCC patients. The inflammation-based prognostic scores included the neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), albumin level, c-reactive protein (CRP) level, modified Glasgow prognostic score (mGPS), and CRP/albumin ratio. The chi-square test and Kaplan–Meier method were used for categorical variable data and overall survival, respectively. A Cox regression model was performed for univariate and multivariable analyses. Results With respect to cervical ESCC, NLR ≥ 2.5 (P = 0.019), PLR ≥ 103 (P = 0.013), CRP value >10 mg/l (P = 0.040), mGPS ≥ 1 (P = 0.040), and CRP/albumin ratio ≥ 9.5 (P = 0.033) were significant predictors of worse overall survival (OS) in the univariate analysis. In a multivariable analysis, PLR ≥ 103 (P = 0.010, HR: 2.66, 95% CI [1.27–5.58]) and mGPS ≥ 1 (P = 0.030, HR: 2.03, 95% CI [1.07–3.86]) were the independent prognostic parameters of worse OS. The prognostic value of these biomarkers in the matched thoracic ESCC patients was similar and compatible with the results in the cervical ESCC group in the univariate and multivariable analyses. Conclusions Our study suggests that these inflammation-based prognostic scores are helpful in clinical practice, and PLR and mGPS may predict the prognosis for locally advanced cervical ESCC patients who receive curative CCRT.
Divide and Conquer for Full-Resolution Light Field Deblurring

The increasing popularity of computational light field (LF) cameras has necessitated the need for tackling motion blur which is a ubiquitous phenomenon in hand-held photography. The state-of-the-art method for blind deblurring of LFs of general 3D scenes is limited to handling only downsampled LF, both in spatial and angular resolution. This is due to the computational overhead involved in processing data-hungry full-resolution 4D LF altogether. Moreover, the method warrants high-end GPUs for optimization and is ineffective for wide-angle settings and irregular camera motion. In this paper, we introduce a new blind motion deblurring strategy for LFs which alleviates these limitations significantly. Our model achieves this by isolating 4D LF motion blur across the 2D subaperture images, thus paving the way for independent deblurring of these subaperture images. Furthermore, our model accommodates common camera motion parameterization across the subaperture images. Consequently, blind deblurring of any single subaperture image elegantly paves the way for cost-effective non-blind deblurring of the other subaperture images. Our approach is CPU-efficient computationally and can effectively deblur full-resolution LFs.
Co-activation of ERK, NF-κB, and GADD45β in Response to Ionizing Radiation*

NF-κB has been well documented to play a critical role in signaling cell stress reactions. The extracellular signal-regulated kinase (ERK) regulates cell proliferation and survival. GADD45β is a primary cell cycle element responsive to NF-κB activation in anti-apoptotic responses. The present study provides evidence demonstrating that NK-κB, ERK and GADD45β are co-activated by ionizing radiation (IR) in a pattern of mutually dependence to increase cell survival. Stress conditions generated in human breast cancer MCF-7 cells by the administration of a single exposure of 5 Gy IR resulted in the activation of ERK but not p38 or JNK, along with an enhancement of the NF-κB transactivation and GADD45β expression. Overexpression of dominant negative Erk (DN-Erk) or pre-exposure to ERK inhibitor PD98059 inhibited NF-κB. Transfection of dominant negative mutant IκB that blocks NF-κB nuclear translocation, inhibited ERK activity and GADD45β expression and increased cell radiosensitivity. Interaction of p65 and ERK was visualized in living MCF-7 cells by bimolecular fluorescence complementation analysis. Antisense inhibition of GADD45β strikingly blocked IR-induced NF-κB and ERK but not p38 and JNK. Overall, these results demonstrate a possibility that NF-κB, ERK, and GADD45β are able to coordinate in a loop-like signaling network to defend cells against the cytotoxicity induced by ionizing radiation.