Does pasteurization inactivate bird flu virus in milk?

ABSTRACTRecently, an outbreak of highly pathogenic avian influenza A (H5N1), which carries the clade 2.3.4.4b hemagglutinin (HA) gene and has been prevalent among North American bird populations since the winter of 2021, was reported in dairy cows in the United States. As of May 24, 2024, the virus has affected 63 dairy herds across nine states and has resulted in two human infections. The virus causes unusual symptoms in dairy cows, including an unexpected drop in milk production, and thick colostrum-like milk. Notably, The US Food and Drug Administration reported that around 20% of tested retail milk samples contained H5N1 viruses, with a higher percentage of positive results from regions with infected cattle herds. Data are scant regarding how effectively pasteurization inactivates the H5N1 virus in milk. Therefore, in this study, we evaluated the thermal stability of the H5 clade 2.3.4.4b viruses, along with one human H3N2 virus and other influenza subtype viruses, including H1, H3, H7, H9, and H10 subtype viruses. We also assessed the effectiveness of pasteurization in inactivating these viruses. We found that the avian H3 virus exhibits the highest thermal stability, whereas the H5N1 viruses that belong to clade 2.3.4.4b display moderate thermal stability. Importantly, our data provide direct evidence that the standard pasteurization methods used by dairy companies are effective in inactivating all tested subtypes of influenza viruses in raw milk. Our findings indicate that thermally pasteurized milk products do not pose a safety risk to consumers.

The calcium-dependent protein kinase CPK16 regulates hypoxia-induced ROS production by phosphorylating the NADPH oxidase RBOHD in Arabidopsis.

Reactive oxygen species (ROS) production is a key event in modulating plant responses to hypoxia and post-hypoxia reoxygenation. However, the molecular mechanism by which hypoxia-associated ROS homeostasis is controlled remains largely unknown. Here, we showed that the calcium-dependent protein kinase CPK16 regulates plant hypoxia tolerance by phosphorylating the plasma membrane-anchored NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) to regulate ROS production in Arabidopsis (Arabidopsis thaliana). In response to hypoxia or reoxygenation, CPK16 was activated through phosphorylation of its Ser274 residue. The cpk16 knockout mutant displayed enhanced hypoxia tolerance, whereas CPK16-overexpressing (CPK16-OE) lines showed increased sensitivity to hypoxic stress. In agreement with these observations, hypoxia and reoxygenation both induced ROS accumulation in the rosettes of CPK16-OEs more strongly than in rosettes of the cpk16-1 mutant or the wild type. Moreover, CPK16 interacted with and phosphorylated the N terminus of RBOHD at four serine residues (Ser133, Ser148, Ser163, and Ser347) that were necessary for hypoxia- and reoxygenation-induced ROS accumulation. Furthermore, the hypoxia-tolerant phenotype of cpk16-1 was fully abolished in the cpk16 rbohd double mutant. Thus, we have uncovered a regulatory mechanism by which the CPK16-RBOHD module shapes ROS production during hypoxia and reoxygenation in Arabidopsis.

A fluorescent aptasensor for enzyme-free and sensitive detection of kanamycin based on entropy-driven strand displacement reaction.

BACKGROUND: Kanamycin is an antibiotic that can easily cause adverse side effects if used improperly. Due to the extremely low concentrations of kanamycin in food, quantitative detection of kanamycin becomes a challenge. As one of the DNA self-assembly strategies, entropy-driven strand displacement reaction (EDSDR) does not require enzymes or hairpins to participate in the reaction, which greatly reduces the instability of detection results. Therefore, it is a very beneficial attempt to construct a highly sensitive and specific fluorescence detection method based on EDSDR that can detect kanamycin easily and quickly while ensuring that the results are effective and stable. RESULTS: We created an enzyme-free fluorescent aptamer sensor with high specificity and sensitivity for detecting kanamycin in milk by taking advantage of EDSDR and the high specific binding between the target and its aptamer. The specific binding can result in the release of the promoter chain, which then sets off the pre-planned EDSDR cycle. Fluorescent label modification on DNA combined with the fluorescence quenching-recovery mechanism gives the sensor impressive fluorescence response capabilities. The research results showed that within the concentration range of 0.1 nM-50 nM, there was a good relationship between the fluorescence intensity of the solution and the concentration of kanamycin. Specificity experiments and actual sample detection experiments confirmed that the biosensor could achieve highly sensitive and specific detection of trace amounts of kanamycin in food, with a detection limit of 0.053 nM (S/N = 3). SIGNIFICANCE: To our knowledge, this is the first strategy to combine EDSDR with fluorescence to detect kanamycin in food. Accurate results can be obtained in as little as 90 min with no enzymes or hairpins involved in the reaction. Furthermore, our enzyme-free biosensing method is straightforward, highly sensitive, and extremely specific. It has many possible applications, including monitoring antibiotic residues and food safety.

Metabolomic analysis, extraction, purification and stability of the anthocyanins from colored potatoes.

Colored potatoes have many health benefits because they are rich in anthocyanins. However, the constituent and property of anthocyanins in colored potatoes have not been systematically studied yet. Herein, metabolomic analysis was carried out to investigate the chemical composition of anthocyanins in the four different colored potatoes. After that, the extract and purification conditions, and the stability of the anthocyanins were further studied. The results indicated that the four colored potatoes contained abundant of polyphenols, flavonoids, and anthocyanins. Cyanidin, delphinidin, and malvidin were identified as the major anthocyanidins in purple potatoes, whereas red potatoes were mainly consisted of pelargonidin and its derivatives. 84.47 mg C3GE/100 g DW of anthocyanins was obtained at the optimal conditions, which could be effectively purified macroporous resin of D101. Moreover, the anthocyanins were sensitive to pH, temperature, light, redox agents, and divalent or trivalent metal ions, but stable to sugars and univalent metal ions.

Engineering a Low-Strain Si@TiSi2@NC Composite for High-Performance Lithium-Ion Batteries.

The huge volume expansion/contraction of silicon (Si) during the lithium (Li) insertion/extraction process, which can lead to cracking and pulverization, poses a substantial impediment to its practical implementation in lithium-ion batteries (LIBs). The development of low-strain Si-based composite materials is imperative to address the challenges associated with Si anodes. In this study, we have engineered a TiSi2 interface on the surface of Si particles via a high-temperature calcination process, followed by the introduction of an outermost carbon (C) shell, leading to the construction of a low-strain and highly stable Si@TiSi2@NC composite. The robust TiSi2 interface not only enhances electrical and ionic transport but also, more critically, significantly mitigates particle cracking by restraining the stress/strain induced by volumetric variations, thus alleviating pulverization during the lithiation/delithiation process. As a result, the as-fabricated Si@TiSi2@NC electrode exhibits a high initial reversible capacity (2172.7 mAh g-1 at 0.2 A g-1), superior rate performance (1198.4 mAh g-1 at 2.0 A g-1), and excellent long-term cycling stability (847.0 mAh g-1 after 1000 cycles at 2.0 A g-1). Upon pairing with LiNi0.6Co0.2Mn0.2O2 (NCM622), the assembled Si@TiSi2@NC||NCM622 pouch-type full cell exhibits exceptional cycling stability, retaining 90.1% of its capacity after 160 cycles at 0.5 C.

Association of sarcopenia with the long-term risk of atrial fibrillation: A prospective cohort study.

The relationship between sarcopenia and the long-term risk of atrial fibrillation (AF) remains unclear. This study recruited a large prospective Caucasian cohort from the UK Biobank. Participants were assessed at baseline with handgrip strength and muscle mass and were categorized into groups of non-sarcopenia, probable sarcopenia, and confirmed sarcopenia. Kaplan-Meier method and Cox proportional hazards model were used to explore the association between sarcopenia and the incidence of AF. The genetic predisposition of AF was assessed by polygenic risk score. Sensitivity analyses were performed to validate the results. A total of 384,433 participants with a median age of 58 years and 54.3% women were enrolled in this study. There were 24,007 cases of new-onset AF over a median follow-up of 12.56 years. The groups of non-sarcopenia, probable sarcopenia, and confirmed sarcopenia accounted for 22,290 (6.1%), 1665 (9.2%), and 52 (11.9%) cases, respectively. Compared with the non-sarcopenia group, participants with probable sarcopenia or confirmed sarcopenia had an 8% (95% CI, 1.03-1.14) or 61% (95% CI, 1.23-2.12) higher risk of AF incidence. The findings remained robust in multiple sensitivity analyses, such as subgroup analysis and further adjustment of genetic predisposition. Notably, the association between sarcopenia and a high AF risk was more pronounced in younger participants, women, and those with valvular heart disease. In conclusion, sarcopenia was associated with a high long-term risk of AF in Caucasians, supporting sarcopenia as a new independent risk factor of AF.

Predictive value of the inconsistency between the residual and post-PCI QFR for prognosis in PCI patients.

Introduction: To investigate the prognostic value of the consistency between the residual quantitative flow ratio (QFR) and postpercutaneous coronary intervention (PCI) QFR in patients undergoing revascularization. Methods: This was a single-center, retrospective, observational study. All enrolled patients were divided into five groups according to the ΔQFR (defined as the value of the post-PCI QFR minus the residual QFR): (1) Overanticipated group; (2) Slightly overanticipated group; (3) Consistent group; (4) Slightly underanticipated group; and (5) Underanticipated group. The primary outcome was the 5-year target vessel failure (TVF). Results: A total of 1373 patients were included in the final analysis. The pre-PCI QFR and post-PCI QFR were significantly different among the five groups. TVF within 5 years occurred in 189 patients in all the groups. The incidence of TVF was significantly greater in the underanticipated group than in the consistent group (P = 0.008), whereas no significant differences were found when comparing the underanticipated group with the other three groups. Restricted cubic spline regression analysis showed that the risk of TVF was nonlinearly related to the ΔQFR. A multivariate Cox regression model revealed that a ΔQFR≤ -0.1 was an independent risk factor for TVF. Conclusions: The consistency between the residual QFR and post-PCI QFR may be associated with the long-term prognosis of patients. Patients whose post-PCI QFR is significantly lower than the residual QFR may be at greater risk of TVF. An aggressive PCI strategy for lesions is anticipated to have less functional benefit and may not result in a better clinical outcome.

Human Stem Cells in Regenerative Medicine.

Modern medicine now has the capacity to improve therapy for many human diseases by introducing adult somatic stem cells that can repair or replace defective or damaged tissues. However, the area is still in an early phase of development, so that all new applications must be carefully designed for maximal safety as well as effectiveness.

A Prospective Multicenter Study on the Additive Value of Contrast-Enhanced Ultrasound for Biopsy Decision of Ultrasound BI-RADS 4 Breast Lesions.

OBJECTIVE: The main aim of this study was to determine whether the use of contrast-enhanced ultrasound (CEUS) could improve the categorization of suspicious breast lesions based on the Breast Imaging Reporting and Data System (BI-RADS), thereby reducing the number of benign breast lesions referred for biopsy. METHODS: This prospective study, conducted between January 2017 and December 2018, enrolled consenting patients from eight teaching hospitals in China, who had been diagnosed with solid breast lesions classified as BI-RADS 4 using conventional ultrasound. CEUS was performed within 1 wk of diagnosis for reclassification of breast lesions. Histopathological results obtained from core needle biopsies or surgical excision samples served as the reference standard. The simulated biopsy rate and cancer-to-biopsy yield were used to compare the accuracy of CEUS and conventional ultrasound (US). RESULTS: Among the 1490 lesions diagnosed as BI-RADS 4 with conventional ultrasound, 486 malignant and 1004 benign lesions were confirmed based on histology. Following CEUS, 2, 395, and 211 lesions were reclassified as CEUS-based BI-RADS 2, 3, and 5, respectively, while 882 (59%) remained as BI-RADS 4. The actual cancer-to-biopsy yield based on US was 32.6%, which increased to 43.4% when CEUS-based BI-RADS 4A was used as the cut-off point to recommend biopsy. The simulated biopsy rate decreased to 73.4%. Overall, in this preselected BI-RADS 4 population, only 2.5% (12/486) of malignant lesions would have been miscategorized as BI-RADS 3 using CEUS-based reclassification. The diagnostic accuracy, sensitivity, and specificity of contrast-enhanced ultrasound reclassification were 57.65%, 97.53%, and 38.35%, respectively. CONCLUSION: Our collective findings indicate that CEUS is a valuable tool in further triage of BI-RADS category 4 lesions and facilitates a reduction in the number of biopsies while increasing the cancer-to-biopsy yield.

How does the status of errant robot affect our desire for contact? - The moderating effect of team interdependence.

Technological breakthroughs such as artificial intelligence and sensors make human-robot collaboration a reality. Robots with highly reliable, specialised skills gain informal status in collaborative teams, but factors such as unstructured work environments and task requirements make robot error inevitable. So how do status differences of errant robots affect the desire for contact, and do team characteristics also have an impact? This paper describes an intergroup experiment using the Experimental Vignette Method (EVM), based on the Expectation Violation Theory, 214 subjects were invited to test the following hypotheses: (1) Errant robot status has an influence on employees' desire for contact and support for robotics research through negative emotions; (2) Team interdependence is a boundary condition for the effect of errant robot status on negative emotions. This paper contributes to the literature on employee reactions to robot errors in human-robot collaboration and provides suggestions for robot status design.

Complex human-robot collaboration inevitably leads to the phenomenon of robot errors. Based on this, we used an Experimental Vignette Method and found that differences in robot status design and human-robot team design features significantly affect employees' cognitive psychology after robot errors and reduce the negative consequences.

Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

PbBeB2O5: A High-Performance Ultraviolet Nonlinear-Optical Crystal with Functional [BeB2O8]8- Group.

High-performance nonlinear-optical (NLO) crystals need to simultaneously meet multiple basic and conflicting performance requirements. Here, by using a partial chemical substitution strategy, the first noncentrosymmetric (NCS) PbBeB2O5 crystal with a BeB2O8 group was synthesized, exhibiting a two-dimensional [BeB2O5]∞ layer constructed by interconnecting BeB2O8 groups and bridged PbO4 with an active lone pair. The crystal shows a promising UV NLO functional feature, including a strong SHG effect of 3.5 × KDP (KH2PO4), large birefringence realizing phase matchability in the whole transparency region from 246 to 2500 nm, a short UV absorption edge of 246 nm, and single-crystal easy growth. Remarkably, theoretical studies reveal that the BeB2O8 group has high nonlinear activity, which could stimulate the discovery of a series of excellent NLO beryllium borates.

Heterologous synthesis of ginsenoside F1 and its precursors in Nicotiana benthamiana.

Ginsenoside F1 has high medicinal values, which is a kind of rare triterpene saponin isolated from Panax plants. The extremely low content of ginsenoside F1 in herbs has limited its research and application in medical field. In this work, we constructed a pathway in tobacco for the biosynthesis of ginsenoside F1 by metabolic engineering. Four enzyme genes (PnDDS, CYP716A47, CYP716S1 and UGT71A56) isolated from Panax notoginseng were introduced into tobacco. Thus, a biosynthetic pathway for ginsenoside F1 synthesis was artificially constructed in tobacco cells; moreover, the four exogenous genes could be expressed in the roots, stems and leaves of transgenic plants. Consequently, ginsenoside F1 and its precursors were successfully synthesized in the transgenic tobacco, compared with Panax plants, the content of ginsenoside F1 in transgenic tobacco was doubled. In addition, accumulation of ginsenoside F1 and its precursors in transgenic tobacco shows organ specificity. Based on these results, a new approach was established to produce rare ginsenoside F1; meanwhile, such strategy could also be employed in plant hosts for the heterologous synthesis of other important or rare natural products.

Discrepancy between arterial oxygen saturation and pulse oximetry measurement in a Chinese pediatric patient cohort.

Background: Increasing evidence suggest a racial bias in pulse oximetry measurement, but this was under investigated in Asian pediatric populations. Methods: Via the Pediatric Intensive Care database, this retrospective study included pediatric patient records of arterial oxygen saturation (SaO2) and oxygen saturation on pulse oximetry (SpO2) measured within 10 min. Discrepancy was examined, and potential predictors of occult hypoxemia (defined as SaO2 <88% with the paired SpO2 ≥92%) as well as its association with outcomes were explored by logistic regression. Results: A total of 390 patients were included with 454 pairs of SaO2-SpO2 readings. The study population consisted of Han Chinese (99.0%) and 43.6% were female. Occult hypoxemia was observed in 20.0% of the patients, with a mean SaO2 of 71.4 ± 15.8%. Potential predictors of occult hypoxemia included female, being first admitted to cardiac ICU, congenital heart disease, increased heart rate, while patients with prior surgery records were less likely to experience occult hypoxemia. Patients with occult hypoxemia had numerically higher in-ICU mortality (16.7% versus 10.9%) and in-hospital mortality (17.9% versus 10.9%), but the associations were not statistically significant. Conclusions: There was a substantial proportion of hypoxemia that was not detected by pulse oximetry in the Chinese pediatric patients, which might be predicted by several characteristics and seemed to associate with mortality.

Differences in Biofilm Formation of Listeria monocytogenes and Their Effects on Virulence and Drug Resistance of Different Strains.

Listeria monocytogenes is recognized as one of the primary pathogens responsible for foodborne illnesses. The ability of L. monocytogenes to form biofilms notably increases its resistance to antibiotics such as ampicillin and tetracycline, making it exceedingly difficult to eradicate. Residual bacteria within the processing environment can contaminate food products, thereby posing a significant risk to public health. In this study, we used crystal violet staining to assess the biofilm-forming capacity of seven L. monocytogenes strains and identified ATCC 19112 as the strain with the most potent biofilm-forming. Subsequent fluorescence microscopy observations revealed that the biofilm-forming capacity was markedly enhanced after two days of culture. Then, we investigated into the factors contributing to biofilm formation and demonstrated that strains with more robust extracellular polymer secretion and self-agglutination capabilities exhibited a more pronounced ability to form biofilms. No significant correlation was found between surface hydrophobicity and biofilm formation capability. In addition, we found that after biofilm formation, the adhesion and invasion of cells were enhanced and drug resistance increased. Therefore, we hypothesized that the formation of biofilm makes L. monocytogenes more virulent and more difficult to remove by antibiotics. Lastly, utilizing RT-PCR, we detected the expression levels of genes associated with biofilm formation, including those involved in quorum sensing (QS), flagellar synthesis, and extracellular polymer production. These genes were significantly upregulated after biofilm formation. These findings underscore the critical relationship between extracellular polymers, self-agglutination abilities, and biofilm formation. In conclusion, the establishment of biofilms not only enhances L. monocytogenes' capacity for cell invasion and adhesion but also significantly increases its resistance to drugs, presenting a substantial threat to food safety.

[Comparison of effectiveness of three surgical methods in treatment of Pauwels type â ¢ femoral neck fracture in young and middle-aged patients].

Objective: To compare the effectiveness of three surgical methods in the treatment of Pauwels type Ⅲ femoral neck fracture in young and middle-aged patients, in order to provide reference for clinical selection of appropriate surgical methods. Methods: The clinical data of 103 patients with Pauwels type Ⅲ femoral neck fracture who met the selection criteria between June 2018 and December 2021 were retrospectively analyzed. The fractures were fixed with hollow screws in an inverted triangular shape (37 cases, hollow screw group), hollow screws in an inverted triangular shape combined with eccentric shaft screw (34 cases, eccentric shaft screw group), and hollow screws in an inverted triangular shape combined with medial support plate (32 cases, support plate group). There was no significant difference in age, gender, cause of injury, body mass index, time from injury to operation, side of the fracture, and Garden classification, whether they were in traction preoperatively, and other baseline data between groups ( P>0.05). The operation time, intraoperative blood loss, the number of fluoroscopy, the length of hospital stay, early postoperative complication and postoperative weight-bearing time of the three groups were recorded. Harris score was used to evaluate joint function at 6 and 12 months after operation, and the difference between the two time points (change value) was calculated for comparison between groups. X-ray films were reviewed to evaluate the quality of fracture reduction (Garden index) and healing, as well as the occurrence of internal fixation failure and femoral head necrosis. Results: The patients of the three groups were successfully completed. Compared with the hollow screw group and the eccentric shaft screw group, the operation time and intraoperative blood loss of the support plate group significantly increased, the number of fluoroscopy reduced, and the quality of fracture reduction was better, the differences were significant ( P<0.05). The operation time, intraoperative blood loss, and the number of fluoroscopy of the hollow screw group were less than those of the eccentric shaft screw group, the differences were significant ( P<0.05). There was no significant difference in the length of hospital stay between groups ( P>0.05). All patients in the three groups were followed up 21-52 months, with an average follow-up time of 36.0 months, and there was no significant difference between groups ( P>0.05). The incisions of all patients healed by first intention. Imaging reexamination showed that there was no significant difference in the incidence of fracture nonunion between groups ( P>0.05). The fracture healing, partial weight-bearing, and full weight-bearing were significantly earlier in the eccentric shaft screw group and the support plate group than in the hollow screw group ( P<0.05). There was no significant difference in change value of Harris score, the incidence of postoperative deep venous thrombosis and femoral head necrosis between groups ( P>0.05); however, the incidence of internal fixation failure in the support plate group and the eccentric shaft screw group was significantly lower than that in the hollow screw group ( P<0.05). The incidence of postoperative lateral thigh irritation in the support plate group was significantly lower than that in the hollow screw group ( P<0.05); there was no significant difference between the eccentric shaft screw group and the other two groups ( P>0.05). The overall incidences of postoperative complications in the eccentric shaft screw group and the support plate group were significantly lower than that in the hollow screw group ( P<0.05). Conclusion: For young and middle-aged patients with Pauwels type Ⅲ femoral neck fracture, compared with simple hollow screw fixation in an inverted triangular shape, combined with medial support plate or eccentric shaft screw internal fixation can shorten the fracture healing time, reduce the incidences of postoperative complication, more conducive to early functional exercise of the affected limb; at the same time, the operation time and blood loss of combined eccentric shaft screw internal fixation are less than those of combined medial support plate internal fixation, so the hollow screw in an inverted triangular shape combined with eccentric shaft screw fixation may be a better choice.

Preserving shape details of pulse signals for video-based blood pressure estimation.

In recent years, imaging photoplethysmograph (iPPG) pulse signals have been widely used in the research of non-contact blood pressure (BP) estimation, in which BP estimation based on pulse features is the main research direction. Pulse features are directly related to the shape of pulse signals while iPPG pulse signals are easily disturbed during the extraction process. To mitigate the impact of pulse feature distortion on BP estimation, it is necessary to eliminate interference while retaining valuable shape details in the iPPG pulse signal. Contact photoplethysmograph (cPPG) pulse signals measured at rest can be considered as the undisturbed reference signal. Transforming the iPPG pulse signal to the corresponding cPPG pulse signal is a method to ensure the effectiveness of shape details. However, achieving the required shape accuracy through direct transformation from iPPG to the corresponding cPPG pulse signals is challenging. We propose a method to mitigate this challenge by replacing the reference signal with an average cardiac cycle (ACC) signal, which can approximately represent the shape information of all cardiac cycles in a short time. A neural network using multi-scale convolution and self-attention mechanisms is developed for this transformation. Our method demonstrates a significant improvement in the maximal information coefficient (MIC) between pulse features and BP values, indicating a stronger correlation. Moreover, pulse signals transformed by our method exhibit enhanced performance in BP estimation using different model types. Experiments are conducted on a real-world database with 491 subjects in the hospital, averaging 60 years of age.

The Odds of Protein Translation Control Under Stress.

Physical or chemical stress is commonly known to inhibit protein translation at the cellular level. Since the process of protein translation requires catalysis by a multi-component machinery containing eukaryotic initiation factors (eIFs) and ribosomes in a sequence of reactions, how the process fails to proceed and whether certain genes can escape such blockade have provoked research efforts. Lines of evidence have demonstrated that phosphorylation of eIF4E or dephosphorylation of 4E-binding proteins (4E-BPs) prevents the formation of the eukaryotic translation initiation factor 4F (eIF4F) complex, whereas phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) due to activation of heme-regulated inhibitor (HRI), general control nonderepressible 2 (GCN2), protein kinase RNA-like endoplasmic reticulum kinase (PERK), or protein kinase R (PKR) by a diverse array of stressors prevents eIF2-GTP-tRNAiMet ternary complex assembly. These signal the abandonment of translation initiation via 5'-7-methylguanine (m7G) cap recognition by eIF4E. Stress can promote cleavage of tRNAs, impediment of rRNA processing, changes in the epitranscriptomic landscape, ribosome stalling or collision, activation of ribosomal surveillance systems, and assembly of the stress granules. Although these events contribute to the general inhibition of protein translation, a few proteins can bypass such negativity and become translated selectively. Such selective protein translation is primarily m7G cap independent through the integrated stress response or Internal Ribosomal Entry Site (IRES). The newly synthesized proteins often influence cell fate, facilitate cell survival, and build endogenous defense. Insights into the general inhibition of protein translation and selective translation of specific proteins will advance our understanding of the etiology or progression of human diseases involving cellular stress from viral infection or inflammation to myocardial infarction, stroke, or neurodegenerative disease.

Quinoline-based compounds can inhibit diverse enzymes that act on DNA.

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine ( 9 ) or methylpiperazine ( 11 ) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) and Clostridioides difficile CamA (which generates N6-methyladenine). Structurally, compounds 9 and 11 specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound 11 elicits DNA damage response via p53 activation. Highlights: Six of fifteen quinoline-based derivatives demonstrated comparable low micromolar inhibitory effects on human cytosine methyltransferase DNMT1, and the bacterial adenine methyltransferases Clostridioides difficile CamA and Caulobacter crescentus CcrM. Compounds 9 and 11 were found to intercalate into a DNA substrate bound by CamA. These quinoline-based derivatives also showed inhibitory activity against various base excision repair DNA glycosylases, and DNA and RNA polymerases. Compound 11 provokes DNA damage response via p53 activation in cancer cells.

Effects of Flavourzyme and Alkaline Protease Treatment on Structure and Allergenicity of Peanut Allergen Ara h 1.

Research background: Peanut allergy poses a significant threat to human health due to the increased risk of long-term morbidity at low doses. Modifying protein structure to affect sensitization is a popular topic. Experimental approach: In this study, the purified peanut allergen Ara h 1 was enzymatically hydrolysed using Flavourzyme, alkaline protease or a combination of both. The binding ability of Ara h 1 to antibodies, gene expression and secretion levels of the proinflammatory factors interleukin-5 and interleukin-6 in Caco-2 cells was measured. Changes in the secondary and tertiary structures before and after treatment with Ara h 1 were analysed by circular dichroism and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Results and conclusions: The results indicated a decrease of the allergenicity and proinflammatory ability of Ara h 1. The evaluation showed that the Flavourzyme and alkaline protease treatments caused particle shortening and aggregation. The fluorescence emission peak increased by 3.4-fold after the combined treatment with both proteases. Additionally, the secondary structure underwent changes and the hydrophobicity also increased 8.95-fold after the combined treatment. Novelty and scientific contribution: These findings partially uncover the mechanism of peanut sensitization and provide an effective theoretical basis for the development of a new method of peanut desensitization.