Miracle-dz/UniFAR-FTUs huggingface dataset:
Polychlorinated dioxins, furans (PCDD/Fs) and dioxin‐like polychlorinated biphenyls (dl‐PCBs) in food from Italy: Estimates of dietaryintake and assessment

Abstract Dietary intake of polychlorinated dioxins and furans (PCDD/Fs) and dioxin‐like polychlorinated biphenyls (dl‐PCBs) from various foods (fish and seafood, meat and meat‐based products, milk and dairy products, hen eggs, olive oil and fats) was investigated for various sex/age groups of the Italian population. The concentrations of PCDD/Fs and dl‐PCBs and their contribution to total TEQ values varied depending on food matrix. Fish (0.50 pg WHO‐TEQ/g wet weight) and seafood (0.16 pg WHO‐TEQ/g wet weight) showed the highest mean concentrations of PCDD/Fs plus dl‐PCBs, followed by meat (1.70 pg WHO‐TEQ/g lipid weight), meat based products (1.03 pg WHO‐TEQ/g lipid weight), milk and dairy products (0.78 pg WHO‐TEQ/g lipid weight), hen eggs (0.71 pg WHO‐TEQ/g lipid weight), fats (0.27 pg WHO‐TEQ/g lipid weight) and olive oil (0.09 pg WHO‐TEQ/g lipid weight). In all samples WHO‐TEQ PCDD/F plus dl‐PCB concentrations fulfilled the European Union food law, except in pork loin samples (1.39 pg WHO‐TEQ/g lipid weight). Differences in exposure depending on the sex/age groups (children > teenagers > adults > elders) and hypotheses considered (lower bound and upper bound) were encountered. Non‐cancer risk values showed a low exposure. Carcinogenicity risk results revealed that highly exposed individuals were distributed over all sex/age groups, even though the proportion of individuals exceeding the safe limit was higher in children. These data once again underline the importance of trying to control the levels of these contaminants in fishery products, particularly in fish, who represents one of the main exposure sources for consumers. Practical Application This paper may help the consumer in making food choices to minimize the exposure risk to dioxins, furans and PCBs
Leu27IGF‐II‐induced hypertrophy in H9c2 cardiomyoblasts is ameliorated by saffron by regulation of calcineurin/NFAT and CaMKIIδ signaling

The insulin‐like growth factor II receptor (IGF‐IIR) induces myocardial hypertrophy under various pathological conditions like diabetes and hypertension via G protein receptors like Gαq or Gαs. Increased expression of the ligand IGF II and IGF‐IIR induces pathological hypertrophy through downstream signaling mediators such as calcineurin, nuclear factor of activated T cells 3 and calcium‐calmodulin (CaM)‐dependent kinase II (CaMKII)‐histone deacetylase 4 (HDAC4). The dried stigma of Crocus sativus L. (saffron) has a long repute as a traditional medicine against various disorders. In the present study, we have investigated whether C. sativus extract (CSE) canameliorate Leu27IGF‐II triggered hypertrophy and have elucidated the underlying mechanism of protection. Additionally, the effects of oleic acid (OA), an activator of calcineurin and CaMKII was investigated thereof. The results demonstrate that CSE can ameliorate Leu27IGF‐II‐induced hypertrophy seemingly through regulation of calcineurin‐NFAT3 and CaMKII‐HDAC4 signaling cascade.
Critical prerequisites for Covid‐19 vaccine acceleration: A developing economy perspective

This study aims to explore the critical prerequisites for accelerating the distribution of the COVID‐19 vaccine in developing countries by using Ghana as a case study. A qualitative study method and content analysis approach was used. In‐depth interviews were conducted with health experts from the Ghana Health Service, World Health Organization (WHO), AstraZeneca, Novartis, and Medtronic Inc. in Ghana. Our analysis of data revealed that new structures, committees, advisory bodies and lines of communication in government evolved during this pandemic and are underlying the current strategy development and decision‐making on COVID‐19 vaccines. The interviews gave insights into six major factors that will aid COVID‐19 vaccine acceleration in Ghana. These factors are: (1) Access to vaccines through delivery, (2) national manufacturing of vaccines, (3) choosing the best vaccine candidates, (4) financial resources, (5) transparency, and (6) vaccine roll‐out and administration. These results could guide policymakers and other relevant stakeholders in prioritizing activities that will aid COVID‐19 vaccine acceleration in Ghana and other lower‐middle‐income countries, tailored to their specific context. As a recommendation, the Ghanaian government should embrace a multisectoral synergy approach to fight the disease. The study also provides insights into how vaccine adoption can be accelerated in the case of future pandemics.
Suicidal Thoughts, Behaviors, and Event-Related Potentials: A Systematic Review and Meta-Analysis

Background Suicidal thoughts and behaviors (STBs) are thought to result from, at least in part, abnormalities in various neural systems. Event-related potentials (ERPs) are a useful method for studying neural activity and can be leveraged to study neural deficits related to STBs; however, it is unknown how effective ERPs are at differentiating various STB groups. The present meta-analysis examined how well ERPs can differentiate (a) those with and without suicidal ideation, (b) those with and without suicide attempts, (c) those with different levels of suicide risk, and (d) differences between those with suicide attempts versus those with suicidal ideation only. Method This meta-analysis included 208 effect sizes from 2,517 participants from 27 studies. We used a random-effects meta-analysis using a restricted maximum likelihood estimator with robust variance estimation. We meta-analyzed ERP-STB combinations that had at least three effect sizes across two or more studies. Results A qualitative review found that for each ERP and STB combination, the literature is highly mixed. Our meta-analyses largely did not find significant relationships between STBs and ERPs. We also found that the literature is likely severely underpowered, with most studies only being sufficiently powered to detect unrealistically large effect sizes. Conclusions Our results provided little-to-no support for a reliable relationship between the ERPs assessed and STBs. However, the current literature is severely underpowered, and there are many methodological weaknesses that must be resolved before making this determination. We recommend large-scale collaboration and improvements in measurement practices to combat the issues in this literature.
Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma

BACKGROUND Targeted arterial infusion of verapamil combined with chemotherapy (TVCC) is an effective clinical interventional therapy for esophageal squamous cell carcinoma (ESCC), but multidrug resistance (MDR) remains the major cause of relapse or poor prognosis, and the underlying molecular mechanisms of MDR, temporal intratumoral heterogeneity, and clonal evolutionary processes of resistance have not been determined. METHODS To elucidate the roles of genetic and epigenetic alterations in the evolution of acquired resistance during therapies, we performed whole-exome sequencing on 16 serial specimens from 7 patients with ESCC at every cycle of therapeutic intervention from 3 groups, complete response, partial response, and progressive disease, and we performed whole-genome bisulfite sequencing for 3 of these 7 patients, 1 patient from each group. RESULTS Patients with progressive disease exhibited a substantially higher genomic and epigenomic temporal heterogeneity. Subclonal expansions driven by the beneficial new mutations were observed during combined therapies, which explained the emergence of MDR. Notably, SLC7A8 was identified as a potentially novel MDR gene, and functional assays demonstrated that mutant SLC7A8 promoted the resistance phenotypes of ESCC cell lines. Promoter methylation dynamics during treatments revealed 8 drug resistance protein-coding genes characterized by hypomethylation in promoter regions. Intriguingly, promoter hypomethylation of SLC8A3 and mutant SLC7A8 were enriched in an identical pathway, protein digestion and absorption, indicating a potentially novel MDR mechanism during treatments. CONCLUSION Our integrated multiomics investigations revealed the dynamics of temporal genetic and epigenetic inter- and intratumoral heterogeneity, clonal evolutionary processes, and epigenomic changes, providing potential MDR therapeutic targets in treatment-resistant patients with ESCC during combined therapies. FUNDING National Natural Science Foundation of China, Science Foundation of Peking University Cancer Hospital, CAMS Innovation Fund for Medical Sciences, Major Program of Shenzhen Bay Laboratory, Guangdong Basic and Applied Basic Research Foundation, and the third round of public welfare development and reform pilot projects of Beijing Municipal Medical Research Institutes.
Translation of human Δ133p53 mRNA and its targeting by antisense oligonucleotides complementary to the 5′-terminal region of this mRNA

The p53 protein is expressed as at least twelve protein isoforms. Within intron 4 of the human TP53 gene, a P2 transcription initiation site is located and this transcript encodes two p53 isoforms: Δ133p53 and Δ160p53. Here, the secondary structure of the 5′-terminal region of P2-initiated mRNA was characterized by means of the SHAPE and Pb2+-induced cleavage methods and for the first time, a secondary structure model of this region was proposed. Surprisingly, only Δ133p53 isoform was synthetized in vitro from the P2-initiated p53 mRNA while translation from both initiation codons occurred after the transfection of vector-encoded model mRNA to HCT116 cells. Interestingly, translation performed in the presence of the cap analogue suggested that the cap-independent process contributes to the translation of P2-initiated p53 mRNA. Subsequently, several antisense oligonucleotides targeting the 5′-terminal region of P2-initiated p53 mRNA were designed. The selected oligomers were applied in in vitro translation assays as well as in cell lines and their impact on the Δ133p53 synthesis and on cell viability was investigated. The results show that these oligomers are attractive tools in the modulation of the translation of P2-initiated p53 mRNA through attacking the 5′ terminus of the transcript. Since cell proliferation is also reduced by antisense oligomers that lower the level of Δ133p53, this demonstrates an involvement of this isoform in tumorigenesis.
Clinical characteristics and predictors of hospitalization among 7,108 ambulatory patients with positive RT-PCR for SARS-CoV-2 during the acute pandemic period

ABSTRACT Objective: To describe baseline characteristics of outpatients with a positive RT-PCR for SARS-CoV-2 and to define whether “red flags” (new-onset fever, dyspnea, and chest pain) can predict clinical worsening during the isolation period. Methods: This was an epidemiological, observational, descriptive study. Between March and September of 2020, all outpatients who tested positive for SARS-CoV-2 at a tertiary medical center located in Santiago de Chile were included. Demographic variables, comorbidities, red flags, and other symptoms were compiled using follow-up surveys at specific time points. The risk of clinical worsening (hospitalization) and adjusted hazard ratios (HRs) were calculated. Results: A total of 7,108 patients were included. The median age was 38 years (range, 0-101), and 52% were men. At baseline, 77% of the patients reported having characteristic symptoms of SARS-CoV-2 infection. The most prevalent onset symptoms were headache (53%), myalgia (47%), and fever (33%). According to the follow-up surveys, the incidence of symptoms decreased during the isolation period; however, 28% of the patients still presented with symptoms on day 14. The risk of hospitalization for patients with new-onset fever and dyspnea during the follow-up period was HR = 7.43 (95% CI, 3.85-14.3, p<0.01) and HR = 5.27 (95% CI, 1.52-18.30; p < 0.01 for both), respectively. New-onset chest pain showed no association with clinical worsening. Conclusions: In this sample of outpatients with a recent diagnosis of SARS-CoV-2 infection, a survey-based monitoring of symptoms was useful to identify those at risk of clinical worsening. New-onset fever and dyspnea during the isolation period were considered as red flags associated with clinical worsening and warrants prompt medical evaluation.
Relevance of animal studies in the toxicological assessment of oil and wax hydrocarbons. Solving the puzzle for a new outlook in risk assessment

Abstract Paraffin waxes and white mineral oils are distinct petroleum products separated from a common feedstock by crystallization, where only n-alkanes, iso- and cyclo-alkanes with a linear backbone of ∼ 20 carbon atoms long, selectively crystalize out from the oil to form the wax, which is solid at room temperature, whereas oils remain liquid. Up until the 90’s, these differences were reflected in separated regulatory assessments. A paradigm shift occurred when Fischer 344 rats (F-344) developed liver epithelioid granuloma following exposure to low and medium viscosity oils or waxes. This lesion was used as common denominator between these products to be jointly assessed under the common term “mineral hydrocarbons – MHC”, obviating compositional differences. This regulatory paradigm dominated for the next 30 years, exacerbated by the EFSA 2012 evaluation using the analytical term “MOSH” (mineral oil saturated hydrocarbons) which encompassed these products under single chromatography fraction. The reconstruction of historical developments, together with recent EFSA-sponsored studies of toxicity and accumulation and supporting literature, has allowed us to understand the etiology of the F-344 rat hepatic epithelioid granuloma, which is presented in an adverse outcome pathway (AOP). Considering chemical composition, it clearly demonstrates that the hepatic effects in F-344 rats caused by linear alkanes of waxes are irrelevant for humans. Waxes are thus not MOSH and should thus be evaluated on their own merit. The term MOSH should not include n-alkanes and be exclusively used to mineral oil fractions when considering their chemical makeup for a relevant human hazard assessment.
Nanotube‐like processes facilitate material transfer between photoreceptors

Neuronal communication is typically mediated via synapses and gap junctions. New forms of intercellular communication, including nanotubes (NTs) and extracellular vesicles (EVs), have been described for non‐neuronal cells, but their role in neuronal communication is not known. Recently, transfer of cytoplasmic material between donor and host neurons (“material transfer”) was shown to occur after photoreceptor transplantation. The cellular mechanism(s) underlying this surprising finding are unknown. Here, using transplantation, primary neuronal cultures and the generation of chimeric retinae, we show for the first time that mammalian photoreceptor neurons can form open‐end NT‐like processes. These processes permit the transfer of cytoplasmic and membrane‐bound molecules in culture and after transplantation and can mediate gain‐of‐function in the acceptor cells. Rarely, organelles were also observed to transfer. Strikingly, use of chimeric retinae revealed that material transfer can occur between photoreceptors in the intact adult retina. Conversely, while photoreceptors are capable of releasing EVs, at least in culture, these are taken up by glia and not by retinal neurons. Our findings provide the first evidence of functional NT‐like processes forming between sensory neurons in culture and in vivo.
The Cycocel effect on flavonoids content and phenylalanine ammonia-lyase (PAL) activity in buckwheat (Fagopyrum esculentum Moench.) plant

Flavonoids are important secondary plant metabolites with many and diverse key functions that belong to largest class of substances produced by plants – phenylpropanoids. These substances are of interested among plant and animal biochemists, plant pathologists, geneticists and biotechnologists. Flavonoids rutin and anthocyanin as herbal compounds characterized by physiological activity of a wide action spectrum: antiulcer, vitamin, antioxidant, stabilizing, ultraviolet radiation protecting, antitumor, tannic, etc. Therefore much attention has been attracted to biosynthesis of flavonoids and methods of its regulation and controlling. We determined concentration (2%) of growth regulator Cycocel (chlormequat chloride, CCC) that significantly raised anthocyanin and rutin levels in buckwheat (Fagopyrum esculentum Moench.) plants. Thin-layer chromatography revealed an increase in total flavonoids content in leaves of test plants, which was: by 3.5 times for rutin and by 8 times for anthocyanin. The same concentration of CCC had induced phenylalanine ammonia-lyase activity by 2 times. Moreover, an increase in the flavonoids content correlated with enzyme activity induction. Thus, the growth regulator Cycocel is an activator of flavonoids metabolism. Treatment by CCC significantly increased content of secondary flavonoid metabolites and activity of phenylalanine ammonia-lyase – flavonoids biosynthesis regulatory enzyme.
Engineered SARS-CoV-2 receptor binding domain improves manufacturability in yeast and immunogenicity in mice

Significance Most of the global population resides in low- and middle-income countries, where current vaccines for COVID-19 remain largely unavailable. For the COVID-19 pandemic, the world will need access to >10 billion doses of vaccines, or more than double the annual volume of vaccines for all other diseases. Many vaccine candidates use the SARS-CoV-2 receptor-binding domain (RBD) antigen. Here, we present an engineered RBD with improved production titers in Pichia pastoris, a yeast commonly used for large-scale, low-cost manufacturing by vaccine manufacturers. The modified RBD also raises an enhanced immune response in mice relative to the Wuhan-Hu-1 sequence used in current candidates. These combined traits make it a promising candidate for next-generation vaccines addressing emerging variants of the virus. Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing cost. These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2. Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.
Loss of Neutrophil Homing to the Periodontal Tissues Modulates the Composition and Disease Potential of the Oral Microbiota

Periodontal disease is considered to arise from an imbalance in the interplay between the host and its commensal microbiota, characterized by inflammation, destructive periodontal bone loss, and a dysbiotic oral microbial community. The neutrophil is a key component of defense of the periodontium: defects in their number or efficacy of function predisposes individuals to development of periodontal disease. ABSTRACT Periodontal disease is considered to arise from an imbalance in the interplay between the host and its commensal microbiota, characterized by inflammation, destructive periodontal bone loss, and a dysbiotic oral microbial community. The neutrophil is a key component of defense of the periodontium: defects in their number or efficacy of function predisposes individuals to development of periodontal disease. Paradoxically, neutrophil activity, as part of a deregulated inflammatory response, is considered an important element in the destructive disease process. In this investigation, we examined the role the neutrophil plays in the regulation of the oral microbiota by analysis of the microbiome composition in mice lacking the CXCR2 neutrophil receptor required for recruitment to the periodontal tissues. A breeding protocol was employed that ensured that only the oral microbiota of wild-type (CXCR2+/+) mice was transferred to subsequent generations of wild-type, heterozygote, and homozygote littermates. In the absence of neutrophils, the microbiome undergoes a significant shift in total load and composition compared to when normal levels of neutrophil recruitment into the gingival tissues occur, and this is accompanied by a significant increase in periodontal bone pathology. However, transfer of the oral microbiome of CXCR2−/− mice into germfree CXCR2+/+ mice led to restoration of the microbiome to the wild-type CXCR2+/+ composition and the absence of pathology. These data demonstrate that the composition of the oral microbiome is inherently flexible and is governed to a significant extent by the genetics and resultant phenotype of the host organism.