Mucosal-associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function.

Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

Delineating cysteine-reactive compound modulation of cellular proteostasis processes.

Covalent modulators and covalent degrader molecules have emerged as drug modalities with tremendous therapeutic potential. Toward realizing this potential, mass spectrometry-based chemoproteomic screens have generated proteome-wide maps of potential druggable cysteine residues. However, beyond these direct cysteine-target maps, the full scope of direct and indirect activities of these molecules on cellular processes and how such activities contribute to reported modes of action, such as degrader activity, remains to be fully understood. Using chemoproteomics, we identified a cysteine-reactive small molecule degrader of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nonstructural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host protein disulfide isomerases. This degrader activity was further potentiated by generalized electrophile-induced global protein ubiquitylation, proteasome activation and widespread aggregation and depletion of host proteins, including the formation of stress granules. Collectively, we delineate the wide-ranging impacts of cysteine-reactive electrophilic compounds on cellular proteostasis processes.

ATRA regulates myoblast differentiation and fusion through the RARα/Pitx2 signaling pathway, causing abnormal development of PFMs in ARM fetal rats.

Anorectal malformation (ARM) is the most common congenital digestive tract anomaly in newborns, and children with ARM often have varying degrees of underdevelopment of the pelvic floor muscles (PFMs). To explore the effects of RARα and Pitx2 on the development of rat PFMs, we constructed a rat ARM animal model using all-trans retinoic acid (ATRA), and verified the expression of RARα and Pitx2 in the PFMs of fetal rats. Additionally, we used rat myoblasts (L6 cells) to investigate the regulatory roles of RARα and Pitx2 in skeletal muscle myoblast differentiation and their interactions. The results indicated a significant decrease in the expression of RARα and Pitx2 in the PFMs of fetal rats with ARM. ATRA can also decrease the expression of RARα and Pitx2 in the L6 cells, while affecting the differentiation and fusion of L6 cells. Knocking down RARα in L6 cells reduced the expression of Pitx2, MYOD1, MYMK, and decreased myogenic activity in L6 cells. When RARα is activated, the decreased expression of Pitx2, MYOD1, and MYMK and myogenic differentiation can be restored to different extents. At the same time, increasing or inhibiting the expression of Pitx2 can counteract the effects of knocking down RARα and activating RARα respectively. These results indicate that Pitx2 may be downstream of the transcription factor RARα, mediating the effects of ATRA on the development of fetal rat PFMs.

TGF-α/EGFR signaling promotes lipopolysaccharide-induced abnormal elastin deposition and alveolar simplification.

Bronchopulmonary dysplasia (BPD) is characterized by shortened secondary septa and fewer, larger alveoli. Elastin deposition to the distal tips of the secondary septa is critical for elongation of the secondary septa. Alveolar myofibroblasts, which are thought to migrate to the septal tips during alveolarization, are mainly responsible for elastin production and deposition. Antenatal exposure to inflammation induces abnormal elastin deposition, thereby increasing the risk of developing BPD. Here, we found that lipopolysaccharide (LPS) significantly increased the expression of transforming growth factor-α (TGF-α) in an LPS-induced rat model of BPD and in LPS-treated human pulmonary epithelial cells (BEAS-2B). In addition, in vitro experiments suggested that LPS upregulated TGF-α expression via toll-like receptor 4 (TLR4)/tumor necrosis factor α-converting enzyme (TACE) signaling. Increased TGF-α levels via its receptor epidermal growth factor receptor (EGFR)-induced lysyl oxidase (LOX) overactivation and cell division cycle 42 (Cdc42) activity inhibition of myofibroblasts. Similarly, in vivo LOX overactivation and inhibition of Cdc42 activity were observed in the lungs of LPS-exposed pups. LOX overactivation led to abnormal elastin deposition, and inhibition of Cdc42 activity disturbed the directional migration of myofibroblasts and disrupted elastin localization. Most importantly, the EGFR inhibitor erlotinib partially rescued LOX overactivation and Cdc42 activity inhibition, and improved elastin deposition and alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that TGF-α/EGFR signaling is critically involved in the regulation of elastin deposition and represents a novel therapeutic target.

PRMT5-mediated homologous recombination repair is essential to maintain genomic integrity of neural progenitor cells.

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.

Lipoprotein-associated phospholipase A2: A paradigm for allosteric regulation by membranes.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) associates with low- and high-density lipoproteins in human plasma and specifically hydrolyzes circulating oxidized phospholipids involved in oxidative stress. The association of this enzyme with the lipoprotein's phospholipid monolayer to access its substrate is the most crucial first step in its catalytic cycle. The current study demonstrates unequivocally that a significant movement of a major helical peptide region occurs upon membrane binding, resulting in a large conformational change upon Lp-PLA2 binding to a phospholipid surface. This allosteric regulation of an enzyme's activity by a large membrane-like interface inducing a conformational change in the catalytic site defines a unique dimension of allosterism. The mechanism by which this enzyme associates with phospholipid interfaces to select and extract a single phospholipid substrate molecule and carry out catalysis is key to understanding its physiological functioning. A lipidomics platform was employed to determine the precise substrate specificity of human recombinant Lp-PLA2 and mutants. This study uniquely elucidates the association mechanism of this enzyme with membranes and its resulting conformational change as well as the extraction and binding of specific oxidized and short acyl-chain phospholipid substrates. Deuterium exchange mass spectrometry coupled with molecular dynamics simulations was used to define the precise specificity of the subsite for the oxidized fatty acid at the sn-2 position of the phospholipid backbone. Despite the existence of several crystal structures of this enzyme cocrystallized with inhibitors, little was understood about Lp-PLA2's specificity toward oxidized phospholipids.

LncRNA sequencing reveals an essential role for the lncRNA-mediated ceRNA network in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) is becoming increasingly common and posing a severe threat to men's health, particularly in developing countries. The function of long non-coding RNAs (lncRNAs) in PSCC progression remains mysterious. Therefore, we explored the significance of lncRNAs in the competing endogenous RNA (ceRNA) network in PSCC tumor progression. The 5 healthy and 6 tumor tissue samples were subjected to lncRNA sequencing. Using miRcode, LncBase, miRTarBase, miRWalk, and TargetScan, we constructed a ceRNA network of differentially expressed lncRNAs, miRNAs, and mRNAs. Our analysis resulted in a ceRNA network consisting of 4 lncRNAs, 18 miRNAs, and 38 mRNAs, whose upstream regulators, the lncRNAs MIR205HG, MIAT, HCP5, and PVT1, were all elevated in PSCC. Immunohistochemical staining confirmed that cell proliferation-related genes TFAP2C, MKI67, and TP63, positively regulated by 4 lncRNAs, were considerably overexpressed in tumor tissues. Immune analysis revealed a significant upregulation in macrophage and exhausted T cell infiltration in PSCC. Our study identified a lncRNA-miRNA-mRNA ceRNA network for PSCC, revealing possible molecular mechanisms involved in the regulation of PSCC progression by key lncRNAs and their connections to the immunosuppressive tumor microenvironment. The ceRNA network provides a novel perspective for elucidating the pathogenesis of PSCC.

LTF ameliorates cartilage endplate degeneration by suppressing calcification, senescence and matrix degradation through the JAK2/STAT3 pathway.

Intervertebral disc degeneration (IDD)-induced cervical and lumbar herniations are debilitating diseases. The function of intervertebral disc (IVD) mainly depends on the cartilage endplate (CEP), which provides support and waste removal. Therefore, IDD stems from the degeneration of CEP. Our study shows that the expression of lactotransferrin (LTF), an iron-binding protein, is significantly decreased in degenerated human and rat CEP tissues. In addition, we found that LTF knockdown promoted calcification, senescence, and extracellular matrix (ECM) degradation in human endplate chondrocytes. Furthermore, the in vivo experiment results confirmed that the JAK2/STAT3 pathway inhibitor AG490 significantly reversed these effects. In addition to investigating the role and mechanism of LTF in CEP degeneration, this study provides a theoretical basis and experimental evidence to improve IDD treatment.

In Situ Pt Migration Enabled Resurrection of Electrocatalyst and Fuel Cell Device.

In direct methanol fuel cells (DMFCs), the poisoning of noble metals is considered to be a major impediment to their commercial development. Here, it is found that the loss of surface Pt is one main reason for the attenuation of catalyst performance during long-time methanol oxidation reaction (MOR). A strategy to realize in situ resurrection of the deactivated catalyst by migrating Pt atoms inside to the surface is innovatively proposed. A high-activity Pt-SnO2 is designed, whose MOR activity is resurrected to 97.4% of the initial value. Based on this, the multiple resurrection of a DMFC device is also achieved for the first time. This work provides a new approach for the solution of catalyst deactivation and the development of sustainable catalysts as well as fuel cells.

A Functionalized Scaffold Facilitates Neurites Extension for Spinal Cord Injury Therapy.

Scaffolds have garnered considerable attention for enhancing neural repairment for spinal cord injury (SCI) treatment. Both microstructural features and biochemical modifications play pivotal roles in influencing the interaction of cells with the scaffold, thereby affecting tissue regeneration. Here, a scaffold is designed with spiral structure and gradient peptide modification (GS) specifically for SCI treatment. The spiral structure provides crucial support and space, while the gradient peptide isoleucine-lysine-valine-alanine-valine (IKVAV) modification imparts directional guidance for neuronal and axonal extension. GS scaffold shows a significant nerve extension induction effect through its interlayer gap and gradient peptide density to dorsal root ganglia in vitro, while in vivo studies reveal its substantial promotion for functional recovery and neural repair. Additionally, the GS scaffold displays impressive drug-loading capacity, mesenchymal stem cell-derived exosomes can be efficiently loaded into the GS scaffold and delivered to the injury site, thereby synergistically promoting SCI repair. Overall, the GS scaffold can serve as a versatile platform and present a promising multifunctional approach for SCI treatment.

Stepwise changes in flavonoids in spores/pollen contributed to terrestrial adaptation of plants.

Protecting haploid pollen and spores against UV-B light and high temperature, 2 major stresses inherent to the terrestrial environment, is critical for plant reproduction and dispersal. Here, we show flavonoids play an indispensable role in this process. First, we identified the flavanone naringenin, which serves to defend against UV-B damage, in the sporopollenin wall of all vascular plants tested. Second, we found that flavonols are present in the spore/pollen protoplasm of all euphyllophyte plants tested and that these flavonols scavenge reactive oxygen species to protect against environmental stresses, particularly heat. Genetic and biochemical analyses showed that these flavonoids are sequentially synthesized in both the tapetum and microspores during pollen ontogeny in Arabidopsis (Arabidopsis thaliana). We show that stepwise increases in the complexity of flavonoids in spores/pollen during plant evolution mirror their progressive adaptation to terrestrial environments. The close relationship between flavonoid complexity and phylogeny and its strong association with pollen survival phenotypes suggest that flavonoids played a central role in the progression of plants from aquatic environments into progressively dry land habitats.

Improved Measurement of the Differential Polarizability Using Co-Trapped Ions.

We present a novel approach for measuring the differential static scalar polarizability of a target ion utilizing a "polarizability scale" scheme with a reference ion co-trapped in a linear Paul trap. The differential static scalar polarizability of the target ion can be precisely extracted by measuring the ratio of the ac Stark shifts induced by an add-on infrared laser shed on both ions. This method circumvents the need for the calibration of the intensity of the add-on laser, which is usually the bottleneck for measurements of the polarizability of trapped ions. As a demonstration, ^{27}Al^{+} (the target ion) and ^{40}Ca^{+} (the reference ion) are used in this work, with an add-on laser at 1068 nm injected into the ion trap along the trap axis. The differential static scalar polarizability of ^{27}Al^{+} is extracted to be 0.416(14) a.u. by measuring the ratio of the ac Stark shifts of both ions. Compared to the most recent result [Phys. Rev. Lett. 123, 033201 (2019)PRLTAO0031-900710.1103/PhysRevLett.123.033201], the relative uncertainty of the differential static scalar polarizability of ^{27}Al^{+} is reduced by approximately a factor of 4, to 3.4%. This improvement is expected to be further enhanced by using an add-on laser with a longer wavelength.

Erratum: Improved Measurement of the Differential Polarizability Using Co-trapped Ions [Phys. Rev. Lett. 133, 033001 (2024)].

This corrects the article DOI: 10.1103/PhysRevLett.133.033001.

Enhanced CO2 Capture through SAPO-34 Impregnated with Ionic Liquid.

The concurrent utilization of an adsorbent and absorbent for carbon dioxide (CO2) adsorption with synergistic effects presents a promising technique for CO2 capture. Here, 1-butyl-3-methylimidazole acetate ([Bmim][Ac]), with a high affinity for CO2, and the molecular sieve SAPO-34 were selected. The impregnation method was used to composite the hybrid samples of [Bmim][Ac]/SAPO-34, and the pore structure and surface property of prepared samples were characterized. The quantity and kinetics of the sorbed CO2 for loaded samples were measured using thermogravimetric analysis. The study revealed that SAPO-34 could retain its pristine structure after [Bmim][Ac] loading. The CO2 uptake of the loaded sample was 1.879 mmol g-1 at 303 K and 1 bar, exhibiting a 20.6% rise compared to that of the pristine SAPO-34 recording 1.558 mmol g-1. The CO2 uptake kinetics of the loaded samples were also accelerated, and the apparent mass transfer resistance for CO2 sorption was significantly reduced by 11.2% compared with that of the pure [Bmim][Ac]. The differential scanning calorimetry method revealed that the loaded sample had a lower CO2 desorption heat than that of the pure [Bmim][Ac], and the CO2 desorption heat of the loaded samples was between 30.6 and 40.8 kJ mol-1. The samples exhibited good cyclic stability. This material displays great potential for CO2 capture applications, facilitating the reduction of greenhouse gas emissions.

The Reduced Gray Matter Volume and Functional Connectivity of the Cerebellum in Type 2 Diabetes Mellitus with High Insulin Resistance.

INTRODUCTION: Insulin resistance is widely thought to be a critical feature in type 2 diabetes mellitus (T2DM), and there is significant evidence indicating a higher abundance of insulin receptors in the human cerebellum than cerebrum. However, the specific structural or functional changes in the cerebellum related to T2DM remain unclear, and the association between cerebellar alterations, insulin resistance, cognition, and emotion is yet to be determined. METHODS: We investigated neuropsychological performance, and structural and functional changes in specific cerebellar subregions in 43 T2DM patients with high insulin resistance (T2DM-highIR), 72 T2DM patients with low insulin resistance (T2DM-lowIR), and 50 controls. Furthermore, the correlation and stepwise multiple linear regression analysis were performed. RESULTS: Compared to the controls, T2DM exhibited lower cognitive scores and higher depressive/anxious scores. Furthermore, T2DM-highIR patients showed reduced gray matter volume (GMV) in the right cerebellar lobules VIIb, Crus I/II, and T2DM showed reduced GMV in left lobules I-IV compared to controls. Additionally, functional connectivity decrease was observed between the right lobules I-V and orbital part of the superior frontal gyrus in T2DM-highIR compared to both T2DM-lowIR and controls. Notably, there were negative correlations between the GMV of the lobules VIIb, Crus I/II, and updated homeostatic model assessment of insulin resistance, and positive correlation with executive/visuospatial performance in T2DM patients. CONCLUSIONS: These results suggest that the cerebellar lobules VIIb, Crus I/II, represent vulnerable brain regions in the context of insulin resistance. Overall, this study offers new insights into the neuropathophysiological mechanisms of brain impairment in patients with T2DM.

Efficacy of Double-Lumen Biliary-Enteric Tube in Enteral Nutrition for Patients with Malignant Obstructive Jaundice.

OBJECTIVE: This study aimed to evaluate the efficacy of a double-lumen biliary-enteric tube (DBET) for enteral nutrition (EN) in individuals with malignant obstructive jaundice (MOJ). METHODS: A retrospective cohort study was conducted using data from a prospectively maintained single-center database, including patients with MOJ. In the intervention group, DBET placement was performed concurrently with percutaneous transhepatic cholangiodrainage and biliary stenting, followed by postoperative EN (DBET-EN). In the control group, deep vein catheterization was undertaken after endoscopic biliary stenting, and parenteral nutrition (PN) was provided. A multivariable generalized linear model was used to assess the association between DBET-EN and 6-month mortality. RESULTS: A total of 74 patients were included in this study, comprising 28 patients in the intervention group (DBET-EN group) and 46 patients in the control group (PN group). Within the 6-month follow-up, 5 patients (17.9%) in the DBET-EN group and 20 (43.5%) in the PN group died. The multivariable generalized linear model demonstrated a significantly reduced 6-month mortality in the DBET-EN group compared to the PN group (adjusted odds ratio [OR]: 0.25, 95% CI: 0.08-0.81, P = 0.020). Secondary outcomes indicated that patients in the DBET-EN group had lower 9-month mortality rates and longer tube retention durations compared to the PN group (all adjusted P < 0.05). Postoperative liver function improved similarly in both groups. At 3, 6, and 9 months postoperatively, patient-generated subjective global assessment (PG-SGA) scores and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) scores were significantly higher in the DBET-EN group than in the PN group (P < 0.05). CONCLUSION: The implementation of DBET for EN in patients in the advanced stage of MOJ proved to be a minimally invasive and safe intervention. It significantly improved patients' nutritional status and quality of life while reducing mortality.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Photoinduced Palladium-Catalyzed Radical Germylative Arylation of Alkenes with Chlorogermanes.

We describe a visible light-induced palladium-catalyzed radical germylative arylation of alkenes with easily accessible chlorogermanes. This protocol provides expedient access to germanium-substituted indolin-2-ones in good to excellent yields under mild reaction conditions. The key step for this strategy lies in the reductive activation of germanium-chloride bonds with an excited palladium complex under visible light irradiation. The involvement of germanium radicals was evidenced by electron paramagnetic resonance spectroscopy experiments.

Intramolecular Hosomi-Sakurai Reaction for the Synthesis of Benzoxasiloles.

A Lewis acid-catalyzed intramolecular Hosomi-Sakurai reaction of o-(allylsilyl)benzaldehyde/ketone has been developed. The reaction proceeds through simultaneous C-Si bond cleavage and C-C bond reconstruction. This protocol provides a rapid approach for the synthesis of allyl-substituted benzoxasiloles under mild conditions.

Utility of enteral nutrition via percutaneous transhepatic cholangiography drainage catheterization in late-stage malignant obstructive jaundice.

Objective: The purpose of this study was to explore the clinical benefits of establishing an enteral nutrition (EN) pathway via percutaneous transhepatic cholangiography drainage (PTCD) catheterization in patients with late-stage malignant obstructive jaundice (MOJ).Methods: We selected 30 patients diagnosed as having late-stage MOJ with malnutrition. A dual-lumen biliary-enteral nutrition tube was placed via PTCD along with a biliary stent implantation. Postoperative EN was provided, and we observed the time taken for tube placement, its success rate, complications, and therapeutic efficacy.Results: Tube placement was successful in all 30 patients with an average procedural time of 5.7 ± 1.4 min with no tube placement complications. Compared to preoperative measures, there was a significant improvement in postoperative jaundice reduction and nutritional indicators one month after the procedure (p < 0.05). Post-placement complications included tube perileakage in 5 cases, entero-biliary reflux in 4 cases, tube blockage in 6 cases, tube displacement in 4 cases, accidental tube removal in 3 cases, and tube replacement due to degradation in 8 cases, with tube retention time ranging from 42 to 314 days, averaging 124.7 ± 37.5 days. All patients achieved the parameters for effective home-based enteral nutrition with a noticeable improvement in their quality of life.Conclusion: In this study, we found that the technique of establishing an EN pathway via PTCD catheterization was minimally invasive, safe, and effective; the tube was easy to maintain; and patient compliance was high. It is, thus, suitable for long-term tube retention in patients with late-stage MOJ.