Miracle-dz/UniFAR-FTUs huggingface dataset:
P53 deficiency affects cholesterol esterification to exacerbate hepatocarcinogenesis

Background and Aims: Cholesterol ester (CE) biosynthesis and homeostasis play critical roles in many cancers, including HCC, but their exact mechanistic contributions to HCC disease development require further study. Approach and Results: Here, we report on a proposed role of tumor suppressor P53 in its repressing ubiquitin‐specific peptidase 19 (USP19) and sterol O‐acyltransferase (SOAT) 1, which maintains CE homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis (HCG) by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and HCG in P53‐deficient mice fed with either a normal chow diet or a high‐cholesterol, high‐fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD‐maintained P53‐deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in the mouse model, the P53‐USP19‐SOAT1 signaling axis is also dysregulated in human HCCs. Conclusions: Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53‐deficient HCC.
Loss of KMT5C Promotes EGFR Inhibitor Resistance in NSCLC via LINC01510-Mediated Upregulation of MET.

EGFR inhibitors (EGFRi) are standard-of-care treatments administered to patients with non-small cell lung cancer (NSCLC) that harbor EGFR alterations. However, development of resistance posttreatment remains a major challenge. Multiple mechanisms can promote survival of EGFRi-treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, the mechanisms involved in bypass signaling activation are understudied and require further elucidation. In this study, we identify that loss of an epigenetic factor, lysine methyltransferase 5C (KMT5C), drives resistance of NSCLC to multiple EGFRis, including erlotinib, gefitinib, afatinib, and osimertinib. KMT5C catalyzed trimethylation of histone H4 lysine 20 (H4K20), a modification required for gene repression and maintenance of heterochromatin. Loss of KMT5C led to upregulation of an oncogenic long noncoding RNA, LINC01510, that promoted transcription of the oncogene MET, a component of a major bypass mechanism involved in EGFRi resistance. These findings underscore the loss of KMT5C as a critical event in driving EGFRi resistance by promoting a LINC01510/MET axis, providing mechanistic insights that could help improve NSCLC treatment. SIGNIFICANCE Dysregulation of the epigenetic modifier KMT5C can drive MET-mediated EGFRi resistance, implicating KMT5C loss as a putative biomarker of resistance and H4K20 methylation as a potential target in EGFRi-resistant lung cancer.
Uncovering Public Perceptions of Older Adults’ Vaccines in Canada: A Study of Online Discussions from National Media Sources

Abstract This study explored how a subsection of Canadians perceive older adults’ vaccines through a qualitative analysis of comments posted in response to national online news articles. We used reflexive thematic analysis to analyse 147 comments from 31 news article comments sections published between 2015 and 2020 from five different national online news sources (CBC, National Post, Global News, Globe & Mail, and Huffington Post Canada) that focused on three older adults’ diseases and vaccines: influenza, pneumococcal pneumonia, and herpes-zoster. Three themes encompassed the similarities and differences in how these three diseases were discussed: (1) the importance of personal experiences on stated stance in vaccine uptake or refusal, (2) questioning vaccine research and recommendations, and (3) criticisms of the government’s unequal vaccine opportunities across different Canadian provinces. Our findings identified that perceptions regarding older adult vaccination were dependent on the vaccine type, and, therefore, we make suggestions for future researchers to build on our findings, particularly the need not to treat the research subject of “older adults’ vaccines” as one entity. Gaining a better understanding of how older adults’ vaccines are perceived in Canada will enable public health professionals to develop effective communication strategies that should ultimately improve vaccination rates for older adults.
A novel hybrid polymer of PCL/Fish gelatin nanofibrous scaffold improves proliferation and differentiation of wharton's jelly-derived mesenchymal cells into islet-like cells.

BACKGROUND Using a different source of stem cells to compensate for the lost beta cells is a promising way to cure diabetic patients. Besides The best efficiency of insulin-producing cells (IPCs) will appear when we culture them in an environment similar to inside the body. Hence, three-dimensional (3D) culture ameliorates the differentiation of diverse kinds of stem cells into IPCs compared to those differentiated in two-dimensional (2D) culture. In this study, we aim to create an ideal differentiation environment by using PCL/Fish gelatin nanofibrous scaffolds to differentiate wharton's jelly-derived mesenchymal cells (WJ-MSCs) to IPCs and compare them with a 2D cultured group. METHODS The evaluation of cellular, molecular, and functional properties of differentiated cells on the 3D and 2D cultures were investigated by several assay such as electron microscopy, quantitative PCR, immunochemistry, western blotting, and ELISA. RESULTS The in vitro studies showed, WJ-MSCs that differentiated in the 3D culture have strong properties of IPCs such as islet-like cells. The expression of pancreatic-specific genes at both RNA and protein levels showed higher differentiation efficacy of 3D culture. Besides, the results of the elisa tests demonstrates that in both groups the differentiated cells are functional and secreted C-peptide and insulin in glucose stimulation, but the secretion of C-peptide and insulin in the 3D culture group was higher than those cultured in 2D groups. CONCLUSION Our findings showed the use of PCL/Fish gelatin nanofibrous scaffolds with optimized differentiation protocols can promote the differentiation of IPCs from WJ-MSCs compared to the 2D culture group.
Activin A promotes hyaluronan production and upregulates versican expression in human granulosa cells

Abstract Hyaluronan is a structural component of the expanded cumulus matrix, and hyaluronan synthase 2 is the major enzyme for the synthesis of hyaluronan in humans. Versican cross-links the hyaluronan-rich matrix to cumulus cells and is critical for successful ovulation. Activin A is a critical intrafollicular regulator of ovarian function. Although activin A has been shown to promote cumulus matrix expansion in mice, the functional role of activin A in the regulation of cumulus expansion in the human ovary remains to be elucidated. Using primary and immortalized human granulosa-lutein cells as study models, we provide the first data showing that activin A increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 in these cells. Additionally, activin A also promoted the expression of the hyaluronan-binding protein versican. Moreover, using inhibitor- and small interfering RNA-mediated inhibition approaches, we found that these stimulatory effects of activin A are most likely mediated through the type I receptor activin receptor-like kinase (ALK4)-mediated Sma- and Mad-related protein (SMAD2)/SMAD3-SMAD4 signaling pathway. Notably, the chromatin immunoprecipitation analyses demonstrated that SMAD4 could bind to human hyaluronan synthase 2 and VERSICAN promoters. The results obtained from this in vitro study suggest that locally produced activin A plays a functional role in the regulation of hyaluronan production and stabilization in human granulosa-lutein cells. Summary sentence The results obtained from this in vitro study suggest that a locally produced intraovarian growth factor (activin A) may play a functional role in the regulation of hyaluronan production and stabilization in the human ovary. Graphical Abstract
Genome-Wide Investigation of Pasteurella multocida Identifies the Stringent Response as a Negative Regulator of Hyaluronic Acid Capsule Production

The bacterial pathogen P. multocida can cause serious disease in production animals, including fowl cholera in poultry, hemorrhagic septicemia in cattle and buffalo, atrophic rhinitis in pigs, and respiratory diseases in a range of livestock. P. multocida produces a capsule that is essential for systemic disease, but the complete mechanisms underlying synthesis and regulation of capsule production are not fully elucidated. A whole-genome analysis using TraDIS was undertaken to identify genes essential for growth in rich media and to obtain a comprehensive characterization of capsule production. ABSTRACT Pasteurella multocida is a Gram-negative capsulated bacterium responsible for a range of diseases that cause severe morbidity and mortality in livestock animals. The hyaluronic acid (HA) capsule produced by P. multocida serogroup A strains is a critical virulence factor. In this study, we utilized transposon-directed insertion site sequencing (TraDIS) to identify genes essential for in vitro growth of P. multocida and combined TraDIS with discontinuous density gradients (TraDISort) to identify genes required for HA capsule production and regulation in this pathogen. Analysis of mutants with a high cell density phenotype, indicative of the loss of extracellular capsule, led to the identification of 69 genes important for capsule production. These genes included all previously characterized genes in the capsule biosynthesis locus and fis and hfq, which encode known positive regulators of P. multocida capsule. Many of the other capsule-associated genes identified in this study were involved in regulation or activation of the stringent response, including spoT and relA, which encode proteins that regulate the concentration of guanosine alarmones. Disruption of the autoregulatory domains in the C-terminal half of SpoT using insertional mutagenesis resulted in reduced expression of capsule biosynthesis genes and an acapsular phenotype. Overall, these findings have greatly increased the understanding of hyaluronic acid capsule production and regulation in P. multocida. IMPORTANCE The bacterial pathogen P. multocida can cause serious disease in production animals, including fowl cholera in poultry, hemorrhagic septicemia in cattle and buffalo, atrophic rhinitis in pigs, and respiratory diseases in a range of livestock. P. multocida produces a capsule that is essential for systemic disease, but the complete mechanisms underlying synthesis and regulation of capsule production are not fully elucidated. A whole-genome analysis using TraDIS was undertaken to identify genes essential for growth in rich media and to obtain a comprehensive characterization of capsule production. Many of the capsule-associated genes identified in this study were involved in the stringent response to stress, a novel finding for this important animal pathogen.
Vegetable oil-based nanoemulsions for the preservation of muscle foods: A systematic review and meta-analysis

Abstract This systematic review and meta-analysis quantified the effects of various vegetable oil-based nanoemulsion (NE) formulations on muscle foods’ microbial and chemical quality by estimating the weighted overall response ratio (R*). Treatment of muscle foods with NE formulations reduced the growth rates of total mesophilic bacteria, total psychrophilic bacteria, lactic acid bacteria, and Enterobacteriaceae by 26.2% (R*=0.738), 19% (R*=0.810), 44.7% (R*=0.553), and 31.8% (R*=0.682) during the storage period, respectively. Moreover, the NE formulations retarded the increasing rates of volatile basic-nitrogen content, lipid and protein oxidation, and lipid hydrolysis by 41.4% (R*=0.586), 34% (R*=0.660), 55% (R*=0.450), and 37.1% (R*=0.629), respectively. The NE formulations prepared from safflower, olive, canola, and sunflower oil were more effective than the other vegetable oils to control microbial growth and slow down chemical changes in muscle foods. The combination of nanoemulsions (NEs) and essential oils (EOs) was more efficient than NEs to preserve muscle foods. Packaging NE-treated muscle foods under anaerobic conditions provided better control of microbial growth and chemical changes than packaging under aerobic conditions. Consequently, a combination of vegetable oil-based NEs and EOs followed by anaerobic packaging is the most effective treatment to improve the quality of muscle foods. Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022. 2057415 .
The effect of myeloperoxidase-oxidized LDL on THP-1 macrophage polarization and repolarization

Macrophages (Mφs) play a crucial role in the development of atherosclerosis by engulfing modified LDL particles and forming foam cells, the hallmark of atherosclerosis. Many studies suggest that myeloperoxidase-oxidized LDL (Mox-LDL) is an important pathophysiological model for LDL modification in vivo. Classically (M1) and alternatively activated (M2) Mφs are both implicated in the process of atherogenesis. Mφs are highly plastic cells whereby they undergo repolarization from M1 to M2 and vice versa. Since little is known about the effects of Mox-LDL on Mφ polarization and repolarization, our study aimed at evaluating the in vitro effects of Mox-LDL at this level through making use of the well-established model of human THP-1-derived Mφs. Resting M0-Mφs were polarized toward M1- and M2-Mφs, then M0-, M1- and M2-Mφs were all treated with physiological concentrations of Mox-LDL to assess the effect of Mox-LDL treatment on Mφ polarization and repolarization. Treatment of M0-Mφs with a physiological concentration of Mox-LDL had no significant effects at the level of their polarization. However, treatment of M1-Mφs with Mox-LDL resulted in a significant reduction in their IL-10 cytokine secretion. Our results point to a potential role of Mox-LDL in increasing the pro-inflammatory state in Mφs through reducing the release of the anti-inflammatory cytokine, IL-10.
Internal Carotid Artery Tortuosity: Impact on Mechanical Thrombectomy

Background: Although tortuosity of the internal carotid artery (ICA) can pose a significant challenge when performing mechanical thrombectomy, few studies have examined the impact of ICA tortuosity on mechanical thrombectomy outcomes. Methods: In a registry-based hospital cohort, consecutive patients with anterior circulation stroke in whom mechanical thrombectomy was attempted were divided into 2 groups: those with tortuosity in the extracranial or cavernous ICA (tortuous group) and those without (nontortuous group). The extracranial ICA tortuosity was defined as the presence of coiling or kinking. The cavernous ICA tortuosity was defined by the posterior deflection of the posterior genu or the shape resembling Simmons-type catheter. Outcomes included first pass effect (FPE; extended Thrombolysis in Cerebral Infarction score 2c/3 after first pass), favorable outcome (3-month modified Rankin Scale score of 0–2), and intracranial hemorrhage. Results: Of 370 patients, 124 were in the tortuous group (extracranial ICA tortuosity, 35; cavernous ICA tortuosity, 70; tortuosity at both sites, 19). The tortuous group showed a higher proportion of women and atrial fibrillation than the nontortuous group. FPE was less frequently achieved in the tortuous group than the nontortuous group (21% versus 39%; adjusted odds ratio, 0.45 [95% CI, 0.26–0.77]). ICA tortuosity was independently associated with the longer time from puncture to extended Thrombolysis in Cerebral Infarction ≥2b reperfusion (β=23.19 [95% CI, 13.44–32.94]). Favorable outcome was similar between groups (46% versus 48%; P=0.87). Frequencies of any intracranial hemorrhage (54% versus 42%; adjusted odds ratio, 1.61 [95% CI, 1.02–2.53]) and parenchymal hematoma (11% versus 6%; adjusted odds ratio, 2.41 [95% CI, 1.04–5.58]) were higher in the tortuous group. In the tortuous group, the FPE rate was similar in patients who underwent combined stent retriever and contact aspiration thrombectomy and in those who underwent either procedure alone (22% versus 19%; P=0.80). However, in the nontortuous group, the FPE rate was significantly higher in patients who underwent combined stent retriever and contact aspiration (52% versus 35%; P=0.02). Conclusions: ICA tortuosity was independently associated with reduced likelihood of FPE and increased risk of postmechanical thrombectomy intracranial hemorrhage. Registration: URL: https://www.clinicaltrials. gov; Unique identifier: NCT02251665.
Unified Algorithm for Multilevel Inverters

Multilevel inverters (MLIs) are broadly classified into symmetrical and asymmetrical types based on the DC-link voltage distribution. Asymmetrical MLIs are further classified into binary, quasi-linear and ternary hybrid inverters based on the geometric progression of the DC-link voltages. This study focuses on a new type of random asymmetrical MLIs (RASMLIs) where the DC links voltages are random and randomness is not pertained to any specific geometric progression. This study proposes an optimised vector search algorithm which is unified for symmetrical, asymmetrical and RASMLI. The concept of gradient-intercept equation and its corresponding Gs is the basis of the algorithm for identifying the proximal vectors. The algorithm determines the maximum DC bus utilisation at which the inverter can effectively produce quality output with minimal total harmonic distortion. As the redundant vectors reduce due to randomness the algorithm also aims at reducing the common-mode voltage with minimum switch transition. To validate the proposed algorithm, a T-type converter with H-bridge modules cascaded along each phase is considered. An experimental prototype of the same was developed and random DC voltages were fed using isolated DC supplies with induction motor as load. Nexys-4 field programmable gate array was used to implement the algorithm.
Plasmodium sporozoite disintegration during skin passage limits malaria parasite transmission

During transmission of malaria‐causing parasites from mosquitoes to mammals, Plasmodium sporozoites migrate rapidly in the skin to search for a blood vessel. The high migratory speed and narrow passages taken by the parasites suggest considerable strain on the sporozoites to maintain their shape. Here, we show that the membrane‐associated protein, concavin, is important for the maintenance of the Plasmodium sporozoite shape inside salivary glands of mosquitoes and during migration in the skin. Concavin‐GFP localizes at the cytoplasmic periphery and concavin(−) sporozoites progressively round up upon entry of salivary glands. Rounded concavin(−) sporozoites fail to pass through the narrow salivary ducts and are rarely ejected by mosquitoes, while normally shaped concavin(−) sporozoites are transmitted. Strikingly, motile concavin(−) sporozoites disintegrate while migrating through the skin leading to parasite arrest or death and decreased transmission efficiency. Collectively, we suggest that concavin contributes to cell shape maintenance by riveting the plasma membrane to the subtending inner membrane complex. Interfering with cell shape maintenance pathways might hence provide a new strategy to prevent a malaria infection.
Stomatal conductance, not biochemistry, drives low temperature acclimation of photosynthesis in Populus balsamifera regardless of nitrogen availability.

Low temperature thermal acclimation may require adjustments to nitrogen and water use to sustain photosynthesis due to slow enzyme functioning and high-water viscosity. However, understanding of photosynthetic acclimation to temperatures below 11 °C is limited. We acclimated Populus balsamifera to 6 and 10 °C (6A and 10A, respectively) and provided the trees with either high or low N fertilizer. We measured net CO2 assimilation rates (Anet ), stomatal conductance (gs ), maximum rates of Rubisco carboxylation (Vcmax ) and electron transport (Jmax ), and dark respiration (Rd ) at leaf temperatures of 2, 6, 10, 14 and 18 °C, along with leaf N concentrations. The 10A trees had higher Anet than the 6A trees at warmer leaf temperatures, which was correlated with higher gs in the 10A trees. The instantaneous temperature responses of Vcmax , Jmax and Rd were similar for trees from both acclimation temperatures. While soil N availability increased leaf N concentrations, this had no effect on acclimation of photosynthesis or respiration. Our results indicate that acclimation below 11 °C occurred primarily through changes in stomatal conductance, not photosynthetic biochemistry, and was unaffected by short-term N supply. Thermal acclimation of stomatal conductance should therefore be a priority for future carbon cycle model development.
Structural basis for the absence of low-energy chlorophylls in a photosystem I trimer from Gloeobacter violaceus

Photosystem I (PSI) is a multi-subunit pigment-protein complex that functions in light-harvesting and photochemical charge-separation reactions, followed by reduction of NADP to NADPH required for CO2 fixation in photosynthetic organisms. PSI from different photosynthetic organisms has a variety of chlorophylls (Chls), some of which are at lower-energy levels than its reaction center P700, a special pair of Chls, and are called low-energy Chls. However, the sites of low-energy Chls are still under debate. Here, we solved a 2.04-Å resolution structure of a PSI trimer by cryo-electron microscopy from a primordial cyanobacterium Gloeobacter violaceus PCC 7421, which has no low-energy Chls. The structure shows the absence of some subunits commonly found in other cyanobacteria, confirming the primordial nature of this cyanobacterium. Comparison with the known structures of PSI from other cyanobacteria and eukaryotic organisms reveals that one dimeric and one trimeric Chls are lacking in the Gloeobacter PSI. The dimeric and trimeric Chls are named Low1 and Low2, respectively. Low2 is missing in some cyanobacterial and eukaryotic PSIs, whereas Low1 is absent only in Gloeobacter. These findings provide insights into not only the identity of low-energy Chls in PSI, but also the evolutionary changes of low-energy Chls in oxyphototrophs.
Isolation‐by‐distance and genetic parentage analysis provide similar larval dispersal estimates

Larval exchange among marine populations is a vital driver of population dynamics and has the potential to inform conservation actions, but accurately measuring dispersal remains challenging. Consequently, empirical dispersal kernels have been measured for only a few marine species. Here, we obtained indirect dispersal estimates using an isolation‐by‐distance (IBD) model in the coral reef fish Elacatinus lori and assessed the accuracy of these estimates by comparing them to direct measurements of dispersal from genetic parentage analysis. Specifically, drawing on the IBD slope and effective population density, we indirectly estimated sigma (σ), the spread of a dispersal distribution. While the spread of the directly measured distribution was σ = 3.93 km (95% CI: 3.29–4.71 km), the spread of the IBD distribution was σ = 4.10 km (95% CI: 3.23–5.03) and σ = 2.90 km (95% CI: 2.26–3.59), assuming a random or monogamous mating system, respectively. Parameterizing Laplace dispersal kernels with these values of σ yielded patterns that were remarkably similar to a kernel fit to the direct parentage data. We also found that, like many marine fishes, E. lori has a large effective population size. However, uncertainty in effective size did not ultimately have a strong effect on the IBD‐based dispersal estimates. Taken together, these findings illustrate that accurate dispersal estimates can be produced by indirect IBD methods and suggest that this more feasible approach to estimating dispersal may be broadly applicable to the study of marine larval dispersal.