Miracle-dz/UniFAR-FTUs huggingface dataset:
Connexins in Cancer: Jekyll or Hyde?

The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic.
Cardiotoxicity of Novel Targeted Hematological Therapies

Chemotherapy-related cardiac dysfunction, also known as cardiotoxicity, is a group of drug-related adverse events negatively affecting myocardial structure and functions in patients who received chemotherapy for cancer treatment. Clinical manifestations can vary from life-threatening arrythmias to chronic conditions, such as heart failure or hypertension, which dramatically reduce quality of life of cancer survivors. Standard chemotherapy exerts its toxic effect mainly by inducing oxidative stress and genomic instability, while new targeted therapies work by interfering with signaling pathways important not only in cancer cells but also in myocytes. For example, Bruton’s tyrosine kinase (BTK) inhibitors interfere with class I phosphoinositide 3-kinase isoforms involved in cardiac hypertrophy, contractility, and regulation of various channel forming proteins; thus, off-target effects of BTK inhibitors are associated with increased frequency of arrhythmias, such as atrial fibrillation, compared to standard chemotherapy. In this review, we summarize current knowledge of cardiotoxic effects of targeted therapies used in hematology.
Looks can be deceiving: speciation dynamics of co‐distributed Angophora (Myrtaceae) species in a varying landscape

Understanding the mechanisms underlying species divergence remains a central goal in evolutionary biology. Landscape genetics can be a powerful tool for examining evolutionary processes. We used genome‐wide scans to genotype samples from populations of eight Angophora species. Angophora is a small genus within the eucalypts comprising common and rare species in a heterogeneous landscape, making it an appropriate group to study speciation. We found A. hispida was highly differentiated from the other species. Two subspecies of A. costata (subsp. costata and subsp. euryphylla) formed a group, while the third (subsp. leiocarpa, which is only distinguished by its smooth fruits and provenance) was supported as a distinct pseudocryptic species. Other species that are morphologically distinct could not be genetically differentiated (e.g., A. floribunda and A. subvelutina). Distribution and genetic differentiation within Angophora were strongly influenced by temperature and humidity, as well as biogeographic barriers, particularly rivers and higher elevation regions. While extensive introgression was found between many populations of some species (e.g., A. bakeri and A. floribunda), others only hybridized at certain locations. Overall, our findings suggest multiple mechanisms drove evolutionary diversification in Angophora and highlight how genome‐wide analyses of related species in a diverse landscape can provide insights into speciation.
Porcine Digestible Peptides (PDP) in Weanling Diets Regulates the Expression of Genes Involved in Gut Barrier Function, Immune Response and Nutrient Transport in Nursery Pigs

Simple Summary Porcine digestive peptides (PDP) are a coproduct of the heparin industry obtained from the enzymatic hydrolysis of porcine intestinal mucosa. They have proven to be a valid substitute for other high quality dietary protein sources for piglets, like spray-dried plasma (SDP), but knowledge about their influence on intestinal function is still scarce. This study found that substituting soybean ingredients with PDP and SDP to the diets of weaned piglets increased growth rate at 14 d post-weaning. In addition, the combination of PDP with SDP increased the expression of certain genes related to intestinal function in the jejunum, which suggests that this combination might have functional properties that contribute to improving the intestinal health of the pigs, although more research is needed to confirm it. Abstract This study was conducted to investigate the effects of dietary supplementation of porcine digestible peptides (PDP), spray-dried plasma (SDP), or a combination of both, on growth performance and the expression of genes related to intestinal function of weaned pigs. A total of 180 piglets (trial 1) and 198 piglets (trial 2) were used to evaluate the partial substitution of soybean ingredients with 2% SDP or 2% PDP (trial 1), and with 3% SDP or the combination of 1% SDP and 2% PDP (SDP-PDP; trial 2) during the pre-starter period (0–14 days). The gene expression of 56 genes was quantified in a qPCR platform in jejunum and ileum samples obtained from piglets 14 d after weaning (trial 2). Piglets fed SDP, PDP and SDP-PDP had a higher body weight (BW), average daily gain (ADG) and feed efficiency (G:F) than the soybean control on day 14 (p < 0.05). In addition, the combination of SDP and PDP upregulated ten genes in jejunum samples (p < 0.05) related to intestinal function. More research is needed to confirm that gene expression upregulation by PDP in combination with SDP has an impact on intestinal function and to elucidate its underlying mechanisms.
Spectroscopy and electrical conductivity of [Au(C3S5)2]n– and [Au(C3Se5)2]n–(n= 0–1) complexes and X-ray crystal structure of [NBun4][Au(C3S5)2]

The complexes [NBun4][Au(C3S5)2][C3S52–= 4,5-dimercapto-1,3-dithiole-2-thionate(2–)] and [NBun4][Au(C3Se5)2][C3Se52–= 4,5-di(hydroseleno)-1,3-diselenole-2-selonate(2–)] were prepared. Oxidation reactions of these complexes with iodine, [ttf]3[BF4]2(ttf˙+= the tetrathiafulvalenium radical cation), and [Fe(cp)2][PF6](cp =η-C5H5) afforded [Au(C3S5)2], [Au(C3Se5)2], [ttf][Au(C3S5)2], [ttf]0.3[Au(C3Se5)2], [Fe(cp)2]0.25[Au(C3S5)2], and [Fe(cp)2]0.2[Au(C3Se5)2], respectively. Controlled-current electrolysis of [NBun4][Au(C3S5)2] in acetonitrile containing an excess of [NBun4][ClO4] afforded [NBun4]0.22[Au(C3S5)2]. The complexes [Au(C3S5)2] and [Au(C3Se5)2] have electrical conductivities of 5.0 × 10–4 and 6.3 × 10–4 S cm–1, the ttf complexes 4.3 × 10–3 and 3.2 × 10–3 S cm–1, respectively, and the other partially oxidized complexes 0.10–0.16 S cm–1 at 25 °C for compacted pellets. Ligand-centred oxidation is believed to occur for both the [Au(C3S5)2]n– and [Au(C3Se5)2]n–(n 3σ(F), converged at R= 0.034.
Protective effect of benfotiamine on methotrexate induced gastric damage in rats

ABSTRACT Methotrexate (MTX) is widely used for treating cancers and inflammatory diseases; it is a potential anti-metabolite and folate antagonist. We investigated potential protective effects of benfotiamine on MTX damage. We used a rat model of MTX induced gastric injury to assess changes in gastric histopathology, oxidative stress and visfatin levels due to MTX treatment. Rats were divided into four groups: an untreated control group, an MTX group treated with a single dose of MTX, a benfotiamine group treated with benfotiamine daily for two weeks, and a benfotiamine + MTX group treated with a single dose of MTX followed by benfotiamine daily for two weeks. Total tissue antioxidant status (TAS), total oxidant status (TOS) and visfatin levels were measured at the end of the experiment. At the end of the experiment, we investigated both visfatin expression and the histopathology of gastric tissues. The mean visfatin level was lower in the MTX group than in the benfotiamine group. The mean tissue TOS levels were higher in MTX group than in the control, benfotiamine or benfotiamine + MTX groups. Significant gastric gland dilation, and erosion and loss of mucosa were found on the gastric surface in the MTX group compared to the control group. The dilation, erosion and mucosal loss were decreased significantly in the benfotiamine + MTX group compared to the MTX group. Compared to the control group, visfatin immunoreactivity was reduced significantly in the MTX group. Decreased visfatin levels appear to play a role in the mechanism of gastric damage. Benfotiamine may be useful for preventing MTX induced gastric injuries.
Hybrid Method of Automated EEG Signals’ Selection Using Reversed Correlation Algorithm for Improved Classification of Emotions †

Based on the growing interest in encephalography to enhance human–computer interaction (HCI) and develop brain–computer interfaces (BCIs) for control and monitoring applications, efficient information retrieval from EEG sensors is of great importance. It is difficult due to noise from the internal and external artifacts and physiological interferences. The enhancement of the EEG-based emotion recognition processes can be achieved by selecting features that should be taken into account in further analysis. Therefore, the automatic feature selection of EEG signals is an important research area. We propose a multistep hybrid approach incorporating the Reversed Correlation Algorithm for automated frequency band—electrode combinations selection. Our method is simple to use and significantly reduces the number of sensors to only three channels. The proposed method has been verified by experiments performed on the DEAP dataset. The obtained effects have been evaluated regarding the accuracy of two emotions—valence and arousal. In comparison to other research studies, our method achieved classification results that were 4.20–8.44% greater. Moreover, it can be perceived as a universal EEG signal classification technique, as it belongs to unsupervised methods.
3D FIB-SEM reconstruction of microtubule–organelle interaction in whole primary mouse β cells

Müller et al. provide the first full 3D reconstructions of microtubule networks in a mammalian cell, the islet β cell. Microtubules are mostly disconnected from centrioles and endomembranes, while associated with cortical insulin granules, highlighting their importance for regulated secretion.
Furin-Mediated Self-Assembly of Olsalazine Nanoparticles for Targeted Raman Imaging of Tumors.

Olsalazine (Olsa) is a broad-spectrum anti-cancer agent acting as a DNA methylation inhibitor. When conjugated to 2-cyano-6-aminobenzothiazole and a peptide substrate specific for the tumor-overexpressed enzyme furin, it can self-assemble into nanoparticles that can be detected by chemical exchange saturation transfer magnetic resonance imaging (CEST MRI). We report here that these nano-assemblies can also be detected with high specificity in furin-overexpressing tumor cells by Raman spectroscopy with a distinct scattering signature and demonstrate the utility of this sensing mechanism in vitro and in vivo. Our findings suggest that Raman spectroscopy could be used for high-resolution image-guided surgery to precisely delineate tumor margins during and after resection in real-time as well as to determine microscopic tumor invasion and multifocal locoregional tumor spread, which are currently impossible to visualize with available imaging technologies including CEST MRI.
Microfluidic Protein Imaging Platform: Study of Tau Protein Aggregation and Alzheimer’s Drug Response

Tau protein aggregation is identified as one of the key phenomena associated with the onset and progression of Alzheimer’s disease. In the present study, we performed on-chip confocal imaging of tau protein aggregation and tau–drug interactions using a spiral-shaped passive micromixing platform. Numerical simulations and experiments were performed in order to validate the performance of the micromixer design. We performed molecular modeling of adenosine triphosphate (ATP)-induced tau aggregation in order to successfully validate the concept of helical tau filament formation. Tau aggregation and native tau restoration were realized using an immunofluorescence antibody assay. The dose–response behavior of an Alzheimer’s drug, methylthioninium chloride (MTC), was monitored on-chip for defining the optimum concentration of the drug. The proposed device was tested for reliability and repeatability of on-chip tau imaging. The amount of the tau protein sample used in our experiments was significantly less than the usage for conventional techniques, and the whole protein–drug assay was realized in less than two hours. We identified that intensity-based tau imaging could be used to study Alzheimer’s drug response. In addition, it was demonstrated that cell-free, microfluidic tau protein assays could be used as potential on-chip drug evaluation tools for Alzheimer’s disease.
Astragalus species: Insights on its chemical composition toward pharmacological applications

Astragalus L. is widely distributed throughout the temperate regions of Europe, Asia, and North America. The genus is widely used in folk medicine and in dietary supplements, as well as in cosmetics, teas, coffee, vegetable gums, and as forage for animals. The major phytoconstituents of Astragalus species with beneficial properties are saponins, flavonoids, and polysaccharides. Astragalus extracts and their isolated components exhibited promising in vitro and in vivo biological activities, including antiaging, antiinfective, cytoprotective, antiinflammatory, antioxidant, antitumor, antidiabesity, and immune‐enhancing properties. Considering their proven therapeutic potential, the aim of this work is to give a comprehensive summary of the Astragalus spp. and their active components, in an attempt to provide new insight for further clinical development of these xenobiotics. This is the first review that briefly describes their ethnopharmacology, composition, biological, and toxicological properties.
Novel neonatal presentation of megalencephaly‐polymicrogyria‐pigmentary mosaicism syndrome (MPPM) related to MTOR mutation: Report of a case

The PI3K/AKT/mTOR signaling pathway is a critical mediator of cell functions. Activating mutations of this pathway are known to disturb normal growth and development, leading to a range of overgrowth and neurologic syndromes. We report a case of megalencephaly‐polymicrogyria‐pigmentary mosaicism syndrome (MPPM) in novel association with MTOR pathogenic variant c.6644C>A (p.Ser2215Tyr) and neonatal evanescent skin findings. This case highlights the importance of a thorough newborn cutaneous examination, as this initial window offers a critical opportunity for potential prognostication and surveillance for neurological sequelae.
IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.
[Impact of the COVID-19 pandemic on Neonatal Screening for Congenital Hypothyroidism.]

OBJECTIVE The purpose of this paper was to describe the diagnosis, treatment and follow-up of patients diagnosed with congenital hypothyroidism (CH) by the Neonatal Screening Program in the Autonomous Community of Madrid during the state of alarm due to the COVID-19 health crisis. METHODS The data were extracted from the retrospective analysis of patients diagnosed with CH and treated at the Clinical Diagnosis and Follow-up Center of CH located in the Pediatric Endocrinology Unit of the General University Hospital Gregorio Marañon. RESULTS During the period between March 14 and June 21, 2020, 7 neonates were diagnosed with congenital hypothyroidism. The Screening Center contacted the Clinical Diagnosis and Follow-up Center urgently, with the location and clinical assessment of the patient on the same day, performing the usual complementary examinations in all of them according to clinical pathway. The median age of diagnosis was 15.5 days (range 7.00-24.00). The subsequent clinical and analytical follow-up was carried out in all cases according to the recommended times. All patients presented normalization of the thyroid function after two weeks of treatment. CONCLUSIONS All patients seen at the Congenital Hypothyroidism Clinical Diagnosis and Follow-up Center during the alarm state period were diagnosed, treated and reevaluated following the usual clinical pathways without incidents. The current epidemiological situation of the COVID-19 pandemic has revealed the correct functioning of the circuit of the Congenital Hypothyroidism Screening Program in less favorable circumstances.
Brassica Bioactives Could Ameliorate the Chronic Inflammatory Condition of Endometriosis

Endometriosis is a chronic, inflammatory, hormone-dependent disease characterized by histological lesions produced by the presence of endometrial tissue outside the uterine cavity. Despite the fact that an estimated 176 million women are affected worldwide by this gynecological disorder, risk factors that cause endometriosis have not been properly defined and current treatments are not efficient. Although the interaction between diet and human health has been the focus of many studies, little information about the correlation of foods and their bioactive derivates with endometriosis is available. In this framework, Brassica crops have emerged as potential candidates for ameliorating the chronic inflammatory condition of endometriosis, due to their abundant content of health-promoting compounds such as glucosinolates and their hydrolysis products, isothiocyanates. Several inflammation-related signaling pathways have been included among the known targets of isothiocyanates, but those involving aquaporin water channels have an important role in endometriosis. Therefore, the aim of this review is to highlight the promising effects of the phytochemicals present in Brassica spp. as major candidates for inclusion in a dietary approach aiming to improve the inflammatory condition of women affected with endometriosis. This review points out the potential roles of glucosinolates and isothiocyanates from Brassicas as anti-inflammatory compounds, which might contribute to a reduction in endometriosis symptoms. In view of these promising results, further investigation of the effect of glucosinolates on chronic inflammatory diseases, either as diet coadjuvants or as therapeutic molecules, should be performed. In addition, we highlight the involvement of aquaporins in the maintenance of immune homeostasis. In brief, glucosinolates and the modulation of cellular water by aquaporins could shed light on new approaches to improve the quality of life for women with endometriosis.
Analysis of a mechanism of the chloride-iodide reaction

We present a detailed analysis of the most recent mechanism of the oscillatory chlorite-iodide reaction proposed by Citri and Epstein. First, we use stoichiometric network analysis (SNA) to determine the complete set of major reaction pathways (extreme currents) of the mechanism under CSTR conditions. Two qualitatively different types of unstable extreme currents are predicted within the mechanism. At three different steady states the dominant extreme currents (EC) are singled out. Subgroups of elementary reactions («dynamic elements»), dominant at different times during a cycle of oscillation, are identified
First Evidence of a Protective Effect of Plant Bioactive Compounds against H2O2-Induced Aconitase Damage in Durum Wheat Mitochondria

In order to contribute to the understanding of the antioxidant behavior of plant bioactive compounds with respect to specific subcellular targets, in this study, their capability to protect aconitase activity from oxidative-mediated dysfunction was evaluated for the first time in plant mitochondria. Interest was focused on the Krebs cycle enzyme catalyzing the citrate/isocitrate interconversion via cis-aconitate, as it possesses a [4Fe-4S]2+ cluster at the active site, making it an early and highly sensitive target of reactive oxygen species (ROS)-induced oxidative damage. In particular, the effect on the aconitase reaction of five natural phenols, including ferulic acid, apigenin, quercetin, resveratrol, and curcumin, as well as of the isothiocyanate sulforaphane, was investigated in highly purified mitochondria obtained from durum wheat (DWM). Interestingly, a short-term (10 min) DWM pre-treatment with all investigated compounds, applied at 150 µM (75 µM in the case of resveratrol), completely prevented aconitase damage induced by a 15 min exposure of mitochondria to 500 µM H2O2. Curcumin and quercetin were also found to completely recover DWM-aconitase activity when phytochemical treatment was performed after H2O2 damage. In addition, all tested phytochemicals (except ferulic) induced a significant increase of aconitase activity in undamaged mitochondria. On the contrary, a relevant protective and recovery effect of only quercetin treatment was observed in terms of the aconitase activity of a commercial purified mammalian isoform, which was used for comparison. Overall, the results obtained in this study may suggest a possible role of phytochemicals in preserving plant mitochondrial aconitase activity, as well as energy metabolism, against oxidative damage that may occur under environmental stress conditions. Further investigations are needed to elucidate the physiological role and the mechanism responsible for this short-term protective effect.
Neural spiking for causal inference

When a neuron is driven beyond its threshold it spikes, and the fact that it does not communicate its continuous membrane potential is usually seen as a computational liability. Here we show that this spiking mechanism allows neurons to produce an unbiased estimate of their causal influence, and a way of approximating gradient descent learning. Importantly, neither activity of upstream neurons, which act as confounders, nor downstream non-linearities bias the results. By introducing a local discontinuity with respect to their input drive, we show how spiking enables neurons to solve causal estimation and learning problems.