Iron metabolism and ferroptosis in nonalcoholic fatty liver disease: what is our next step?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD.

Targeting UBR5 inhibits postsurgical breast cancer lung metastases by inducing CDC73 and p53 mediated apoptosis.

UBR5 is a HECT domain E3 ubiquitin ligase that is frequently amplified in breast, ovarian and prostate cancers. Heightened UBR5 expression plays a profound role in tumor growth through immune-dependent mechanisms; however, its mode of action in driving tumor metastasis has not been definitively delineated. Herein, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in mouse lungs without the continuous influence of the primary lesion. In vitro, Ubr5 knockdown induces morphological and molecular changes characteristic of epithelial-mesenchymal transition (EMT). In vivo, UBR5 promotes lung metastasis in an E3 ubiquitin ligase-dependent manner. Moreover, doxycycline-induced UBR5 expression knockdown in metastatic cells in the lungs, following removing the primary tumors, resulted in increased apoptosis, decreased proliferation and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73. In human triple-negative breast cancer (TNBC) patient specimens, a strong inverse correlation was observed between UBR5 and CDC73 protein levels, with reduced CDC73 expression at metastatic sites compared to primary lesions. Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.

Palladium catalyzed stereoselective intramolecular [3 + 2] cycloaddition reactions of (E) & (Z)-ene-vinylidenecyclopropanes.

A palladium-catalyzed ring-opening cyclization of (E) & (Z)-ene-vinylidenecyclopropanes has been developed via an intramolecular [3 + 2] cycloaddition process in the presence of a sterically bulky biaryl phosphine ligand, stereoselectively affording fused cis- & trans-bicyclo[4.3.0] skeletal products in good yields with a broad substrate scope and good functional tolerance. A plausible reaction mechanism was proposed on the basis of previous work and the DFT calculations.

Human MD2 deficiency-an inborn error of immunity with pleiotropic features.

BACKGROUND: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. OBJECTIVE: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. METHODS: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. RESULTS: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. CONCLUSIONS: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting.

Mechanistic Studies on Rhodium-Catalyzed Chemoselective Cycloaddition of Ene-Vinylidenecyclopropanes: Water-Assisted Proton Transfer.

Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

The relationship between preschool teacher trait mindfulness and teacher-child relationship quality: the chain mediating role of emotional intelligence and empathy.

The teacher-child relationship plays an important role in children's future development. However, the existing research mainly focuses on the influence of preschool teachers' external conditions on the teacher-student relationship, while the research on the influence of teachers' internal psychological characteristics on the teacher-student relationship is relatively lacking. In this study, three hundred and seventeen preschool teachers were tested were tested with Five Facet Mindfulness Questionnaire, Emotional Intelligence Scale, Chinese Interpersonal Response Index, and Teacher-student Relationship Scale. The results showed that trait mindfulness positively predicted the quality of parent-teacher relationship (ß = 0.173, p = 0.026). Emotional intelligence played a mediating role in trait mindfulness and teacher-child relationship quality (ß = 0.118, p = 0.004), and empathy played a mediating role in trait mindfulness and teacher-child relationship quality (ß = 0.112, p = 0.001). Meanwhile, emotional intelligence and empathy played a chain mediating role in trait mindfulness and parent-teacher relationship quality (ß = 0.044, p = 0.038). On the one hand, this study enriches attachment theory. The conclusions of this study verify the diversity of proximal factors in attachment theory, and confirm the influence of teachers' own characteristics and abilities on the teacher-child relationship quality. On the other hand, by exploring the factors affecting the teacher-child relationship quality, we can find ways to improve teacher-child relationship from a new perspective, and then provide some new methods and approaches for improving the quality of preschool teacher-child relationship.

Near-field radiative heat transfer in three-body Weyl semimetals.

We investigate the near-field radiative heat transfer in a three-body system made of Weyl semimetals. At infinitesimal temperature gradient, the rotation of the middle and the right bodies leads to heat transfer suppression, enabling thermal switching with considerably enhanced heat flux but slightly smaller ratio than two-body system without the middle body, due to stronger cavity surface plasmon polariton modes and their mismatch caused by relative rotation. By further moving the middle body to induce asymmetric cavity sizes, the three-body system can achieve a switching ratio exceeding the two-body counterpart due to asymmetric cavity modes coupling. As the temperature gradient increases to 200 K, the highest switching ratio by optimally tuning the rotation and cavity size asymmetry decreases slightly yet still outperforms the two-body system. Our results provide important understanding of the near-field radiative heat transfer in many-body systems consisting of Weyl semimetals.

Near-field radiative heat transfer in three-body Weyl semimetals: erratum.

This erratum corrects a typographical error in Eq. (4) of our published paper [Opt. Express30(18), 31584 (2022).10.1364/OE.465017]. This misprint does not influence the results and conclusions presented in the original Article.

Fbxw17 is dispensable for viability and fertility in mice.

BACKGROUND: Skp1-Cullin-F-box (SCF) E3 ligase complex plays an important role in regulating spermatogenesis and fertility in mice. As a member of F-box proteins, the function of F-box and WD-40 domain protein 17 (Fbxw17) during spermatogenesis and fertility is unclear. In this study, we illustrate its function for spermatogenesis and fertility. METHODS AND RESULTS: Here, we generated the Fbxw17 knockout (KO) mouse model by using the CRISPR/Cas9 system and analyzed the meiotic process and the fertility. Then, our results demonstrated that testis and sperm in the Fbxw17 KO mice had normal morphology. The testis weight, sperm count and fertility of Fbxw17 KO mice showed no significant difference compared with the wild-type mice. Subsequently, histological analysis of Fbxw17 KO mice revealed apparently normal germ cells of all stages and mature spermatozoa. Meanwhile, nuclear spread analysis showed that the synaptonemal complex formation and DSB repair proceeded normally in Fbxw17-deficient spermatocytes. Furthermore, we didn't find defects in the meiotic prophase I spermatocytes and germ cells showed no apparent apoptosis in Fbxw17 KO mice. CONCLUSIONS: Our results show that Fbxw17 is dispensable for fertility in mice.

Genetic polymorphism rs8193036 of IL17A is associated with increased susceptibility to pulmonary tuberculosis in Chinese Han population.

Th17 cells play a key role in immunity against Mycobacterium tuberculosis, our previous research showed that reduced Th17 responses were associated with the severe outcome of Mtb infection. The associations between IL17A polymorphisms and susceptibility of TB has been reported, but the results are inconsistent and the underlying mechanisms is unknown. In this study, we identified a genetic variation (rs8193036) in the promoter region of IL17A is associated with susceptibility to TB. The minor allele T frequency of rs8193036 was significantly different between patients with active TB (29.7%) and healthy controls (32.3%) (OR = 0.81; 95%CI, 0.71-0.93; P = 0.0026). Peripheral blood mononuclear cells from individuals carrying rs8193036CC genotypes produced significantly lower amount of IL17A upon CD3/28 stimulation compared to the individuals carrying rs8193036TT genotypes. Functional assay by reporter luciferase activity and EMSA demonstrated that rs8193036C exhibited significantly lower promotor transcription activities. In conclusion, our study confirmed that IL17A (rs8193036) is a functional SNP that could regulate gene expression though influencing transcription factor binding activity.

TSV-integrated thermoelectric cooling by holey silicon for hot spot thermal management.

The trends toward higher power, higher frequency, and smaller scale electronics are making heat dissipation ever more challenging. Passive thermal management based on high thermal conductivity materials or through-silicon vias (TSVs) may not provide sufficient cooling for hot spots reaching 1 kW cm-2, and active thermal management by thermoelectric cooling (TEC) may require large power consumption or suffer from a large off-state thermal resistance of thermoelectric materials. Here we address these issues by integrating a holey silicon-based TEC with a TSV that directly draws heat from a hot spot to combine active and passive cooling approaches. Our simulations of the TSV-integrated TEC demonstrate exceptional cooling performance, which reduces the hot spot temperature from 154 °C to 68 °C while dissipating a heat flux of 1 k W cm-2 and consuming 0.5 W for TEC operation. The off-state hot spot temperature, 154 °C, is 24 °C lower than that of the same TEC with no TSV, and the on-state hot spot temperature, 68 °C, is 67 °C lower than that of the same TEC with no TSV. We also investigate the cooling prospects of metal-filled holey silicon by modeling the electron-phonon coupling and size dependent transport phenomena, which can further increase the thermal conductivity anisotropy and improve the TEC performance depending on the metal-to-silicon interfacial resistance. These results show the combined passive and active cooling in TSV-integrated TEC offers effective hot spot thermal management solutions for advanced electronics.

A new technique for promoting cyclic utilization of cyclodextrins in biotransformation.

Cyclodextrins (CDs) can improve the productivity of steroid biotransformation by enhancing substrate solubility. CDs can be recycled by grafting them with appropriate carriers. Loofah fiber is an excellent grafting material for CDs, and can be applied to the biotransformation and recycling of ß-cyclodextrin (ß-CD). In this work, a technique for recycling ß-CD in cortisone acetate (CA) biotransformation by Arthrobacter simplex CPCC 140451 was studied. Loofah fiber-grafted ß-CD (LF-ß-CD) was prepared using epichlorohydrin, which is a cross-linking agent. The grafting yield of ß-CD was 74.8 mg g-1 dried fibers. LF-ß-CD could increase the solubility of CA and enhance biotransformation. The initial conversion rate of CA was 1.5-fold higher than that of the blank group. LF-ß-CD was also used in biocatalytic reactions for eight cycles, and it maintained the conversion ratio of CA at approximately 90%. Given the above positive results, LF-ß-CD can be utilized in biotechnological recycling applications. This method can also be applied to CD derivatives and hydrophobic compounds.

Palladium-catalyzed selective C-C bond cleavage of keto-vinylidenecyclopropanes: construction of structurally rich dihydrofurans and tetrahydrofurans.

Palladium-catalyzed selective cleavage of the distal C-C bond and proximal C-C bond of keto-vinylidenecyclopropanes by altering the sterically bulky phosphine ligands has been realized. The proximal C-C bond cleavage can be achieved by using dtbpf as a phosphine ligand, affording bicyclic products containing dihydrofuran skeletons in good yields along with broad substrate scope. In proximal C-C bond cleavage reactions, the eight-membered cyclic palladium intermediate plays a key role in the reaction. The [3 + 2] cycloaddition of keto-vinylidenecyclopropanes through the distal C-C bond cleavage can be effectively accomplished with t BuXPhos as a phosphine ligand and ZnCl2 as an additive, delivering bicyclic products containing tetrahydrofuran skeletons in good yields. The further transformation of these bicyclic products has been demonstrated, and the reaction mechanisms of two different C-C bond cleavage reactions have been investigated by control experiments and DFT calculations.

Robust acoustic directional sensing enabled by synergy between resonator-based sensor and deep learning.

We demonstrate enhanced acoustic sensing arising from the synergy between resonator-based acoustic sensor and deep learning. We numerically verify that both vibration amplitude and phase are enhanced and preserved at and off the resonance in our compact acoustic sensor housing three cavities. In addition, we experimentally measure the response of our sensor to single-frequency and siren signals, based on which we train convolutional neural networks (CNNs). We observe that the CNN trained by using both amplitude and phase features achieve the best accuracy on predicting the incident direction of both types of signals. This is even though the signals are broadband and affected by noise thought to be difficult for resonators. We attribute the improvement to a complementary effect between the two features enabled by the combination of resonant effect and deep learning. This observation is further supported by comparing to the CNNs trained by the features extracted from signals measured on reference sensor without resonators, whose performances fall far behind. Our results suggest the advantage of this synergetic approach to enhance the sensing performance of compact acoustic sensors on both narrow- and broad-band signals, which paves the way for the development of advanced sensing technology that has potential applications in autonomous driving systems to detect emergency vehicles.

Evaluating the relative importance of different blood pressure indices in screening for NAFLD: a survey report based on a health examination population.

Objective: While hypertension is a well-recognized risk factor for non-alcoholic fatty liver disease (NAFLD), the specific roles of various common blood pressure measurements [diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), mean arterial pressure (MAP)] in detecting NAFLD and evaluating the associated risk in adults remain unclear. Methods: A retrospective analysis was conducted on 14,251 adult participants undergoing health screenings in the NAfld in the Gifu Area, Longitudinal Analysis project (NAGALA). Following the Z-transformation of the independent variables, we evaluated the relationships between the four blood pressure indices and NAFLD through multivariable logistic regression models. This analysis documented the odds ratio (OR) and 95% confidence interval (CI) for each standard deviation (SD) increase. Additionally, the effectiveness of these indices in identifying NAFLD was comparatively analyzed using receiver operating characteristic (ROC) curves. Results: After adequately adjusting for confounders, all blood pressure indices except PP showed a positive correlation with NAFLD. For each SD increment, MAP had the strongest association with NAFLD compared to SBP and DBP. This finding was confirmed in populations without exercise habits, under 60 years of age, with normal blood pressure, and in non-obese groups. Furthermore, based on ROC analysis, MAP was found to have the highest accuracy in identifying NAFLD compared to the other three blood pressure indices. Conclusion: Among the four blood pressure indices evaluated, MAP demonstrates the greatest efficacy in identifying NAFLD and assessing its associated risk. These findings underscore the potential of MAP as the most promising blood pressure index for screening NAFLD.

TEMPO-Grafted Polystyrene/Polymethacrylate Organosiloxane Janus Nanohybrids as Efficient Pickering Interfacial Catalyst for Selective Aerobic Oxidation of Cinnamyl Alcohol.

The novel 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) groups immobilized on functional polymers or nanoparticles emerged as potential Pickering interfacial catalysts (PICs) for effective catalysis in biphasic systems. In this study, a snowman-shaped Janus-structured polymer with TEMPO-anchored nanohybrid particles (SM-JPP-TEMPO) was prepared and employed as a potential PIC in the Anelli-Montanari system for the selective oxidation of alcohol. The amphiphilic character of SM-JPP-TEMPO particles plays a dual role as an emulsifier and catalyst in the Pickering emulsion. As a result, it enables smaller droplets (102 µm) at the water-in-oil (W/O) interface and reduces the interfacial tension from 26.58 to 17.38 mN/m, which improves the stability of the Pickering emulsion system. This constructed Pickering emulsion microreactor offers a larger interface contact area and shortens the mass transfer distance of the substrate of cinnamyl alcohol, which significantly enhances the catalytic conversion at the Anelli-Montanari oxidation system, thus achieving remarkable conversion efficiency of (92.3%) with excellent selectivity (99%) in static (stirring-free) condition. It was found that the Janus nanohybrid catalyst (SM-JPP-TEMPO) enhanced 1.29-fold catalytic efficiency compared to the TEMPO grafted spherical polystyrene nanoparticle (PS-NPs-TEMPO) catalyst (72%). Moreover, after seven consecutive cycles, the Janus nanocatalyst (SM-JPP-TEMPO) maintained the conversion significantly. Hence, these results collectively highlight that the amphiphilic SM-JPP-TEMPO catalyst provides an efficient and eco-friendly strategy for the intensification of liquid-liquid biphasic reaction systems for potential applications in industries.

Application of a centrifugal disc fertilizer spreading system for UAVs in rice fields.

Unmanned aerial vehicle (UAV) granular fertilizer spreading technology has been gradually applied in agricultural production. However, in the process of spreading operation, the actual influence effect of each factor in field operation is still unclear. Based on the self-developed UAV fertilizer spreading system, this paper explores the effects of three factors, the baffle retraction (B), spreading disc speed (D), and UAV flight altitude (H), on the granular fertilizer spreading effect in the actual field scenarios through the orthogonal test and taking the coefficient of variation (Cv) and relative error of fertilizer application rate (λ) as the evaluation indexes. The results showed that the optimal factor level combination of Cv was 11.23 % for BbDbHa (the baffle retraction is 6 %, spreading disc speed is 600r/min, and UAV flight height is 1.5 m) at UAV flight speed of 2 m/s. The best factor level combination for λ was BbDbHb of 7.99 % (the baffle retraction is 6 %, spreading disc speed is 600r/min, and UAV flight height is 2 m). In addition, by analysing the influence of the weather and the vortex of the rice canopy on the actual spreading effect, it was found that the weather has less influence on the spreading effect of this system, while the vortex caused by the airflow of the UAV rotor has a certain influence on the spreading effect, which is also relatively easy to ignore in fertilizer spreading operations. The results of the study can be used to explore the operational effects of actual fertilizer application by UAVs in rice field, which will help promote the development of UAV spreading technology and provide a reference for precision fertilizer application through agricultural aviation.

Integrin αvß3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.

Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvß3 via upregulation of the ß3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvß3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. SIGNIFICANCE: Upregulation of integrin αvß3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related commentary by Rainero, p. 1543.

Financial impact of cost of capital on tourism-based SMEs in COVID-19: implications for tourism disruption mitigation.

Opportunities for funding Tourism SMEs are emerging globally due to the expansion of tourism sector. However, it is still being determined how these financial arrangements will be controlled at more significant sizes equitably. In the contemporary period, E7 economy is deficient in producing the financial resources to ensure the availability of funds for the acquisition of funds for tourism-based SMEs. However, this research tested the empirical position of cost of debt in E-7 economies during COVID-19 crises. Study findings have shown significant outcomes between the constructs. The variation of conditions, structural uncertainty, transection systems, and variation in support by the financial institution for tourism-based SMEs are the main reasons that lessen borrowing and lending system of funds, from banks to SMEs. However, theorists must revisit the transaction system of debt financing for SMEs. Policymakers are suggested to develop viable and SME system-friendly policies to finance through debt capital from the banks in the time of structural imposed crises, like COVID-19.

The gut microbiome: A line of defense against tuberculosis development.

The tuberculosis (TB) burden remains a significant global public health concern, especially in less developed countries. While pulmonary tuberculosis (PTB) is the most common form of the disease, extrapulmonary tuberculosis, particularly intestinal TB (ITB), which is mostly secondary to PTB, is also a significant issue. With the development of sequencing technologies, recent studies have investigated the potential role of the gut microbiome in TB development. In this review, we summarized studies investigating the gut microbiome in both PTB and ITB patients (secondary to PTB) compared with healthy controls. Both PTB and ITB patients show reduced gut microbiome diversity characterized by reduced Firmicutes and elevated opportunistic pathogens colonization; Bacteroides and Prevotella were reported with opposite alteration in PTB and ITB patients. The alteration reported in TB patients may lead to a disequilibrium in metabolites such as short-chain fatty acid (SCFA) production, which may recast the lung microbiome and immunity via the "gut-lung axis". These findings may also shed light on the colonization of Mycobacterium tuberculosis in the gastrointestinal tract and the development of ITB in PTB patients. The findings highlight the crucial role of the gut microbiome in TB, particularly in ITB development, and suggest that probiotics and postbiotics might be useful supplements in shaping a balanced gut microbiome during TB treatment.