INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling.

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4+ T and CD8+ T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-γ (IFN-γ) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-γ-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade.

Effects of cellulase treatment on properties of lignocellulose-based biochar.

As the most abundant renewable carbon source, lignocellulose holds potential as a raw material for biofuels and biochar. The components required for biofuel production differ from those for biochar, so combining processes can reduce costs. Biofuel preparation necessitates cellulase treatment of lignocellulose. This study examines the effects of various enzyme treatment conditions (dosage, time, temperature) on lignocellulose, focusing on the properties of biochar derived from it (BC-SR). A mathematical model was constructed to study the relationship between enzyme treatment conditions and BC-SR properties. BC-SR exhibited high adsorption selectivity for bisphenol A and outperformed untreated biochar in fixed-bed column experiments, demonstrating greater removal efficiency and structural integrity. This study provides insights into the impact of enzymatic treatment on biochar and offers a cost-effective method for producing stable, efficient biochar. Additionally, a highly persistent biochar can enter the carbon trading market as a carbon-neutral technology, further realizing economic and environmental benefits.

A vascular endothelial growth factor-loaded chitosanhyaluronic acid hydrogel scaffold enhances the therapeutic effect of adipose-derived stem cells in the context of stroke.

Adipose-derived stem cell, one type of mesenchymal stem cells, is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery. However, its application has been limited by the complexities of the ischemic microenvironment. Hydrogel scaffolds, which are composed of hyaluronic acid and chitosan, exhibit excellent biocompatibility and biodegradability, making them promising candidates as cell carriers. Vascular endothelial growth factor is a crucial regulatory factor for stem cells. Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells, thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke. Here, we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells. Subsequently, we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemia-reperfusion injury. When loaded with adipose-derived stem cells, this vascular endothelial growth factor-loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology. Further in vivo experiments revealed that this vascular endothelial growth factor-loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells, leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion. It also helped maintain mitochondrial integrity and axonal morphology, greatly improving rat motor function and angiogenesis. Therefore, utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.

Proteomic characterization of murine hematopoietic stem progenitor cells reveals dynamic fetal-to-adult changes in metabolic-related pathways.

Hematopoietic stem progenitor cells (HSPCs) give rise to the hematopoietic system, maintain hematopoiesis throughout the lifespan, and undergo molecular and functional changes during their development and aging. The importance of hematopoietic stem cell (HSC) biology has led to their extensive characterization at genomic and transcriptomic levels. However, the proteomics of HSPCs throughout the murine lifetime still needs to be fully completed. Here, using mass spectrometry (MS)-based quantitative proteomics, we report on the dynamic changes in the proteome of HSPCs from four developmental stages in the fetal liver (FL) and the bone marrow (BM), including E14.5, young (2 months), middle-aged (8 months), and aging (18 months) stages. Proteomics unveils highly dynamic protein kinetics during the development and aging of HSPCs. Our data identify stage-specific developmental features of HSPCs, which can be linked to their functional maturation and senescence. Our proteomic data demonstrated that FL HSPCs depend on aerobic respiration to meet their proliferation and oxygen supply demand, while adult HSPCs prefer glycolysis to preserve the HSC pool. By functional assays, we validated the decreased mitochondrial metabolism, glucose uptake, reactive oxygen species (ROS) production, protein synthesis rate, and increased glutathione S-transferase (GST) activity during HSPC development from fetal to adult. Distinct metabolism pathways and immune-related pathways enriched in different HSPC developmental stages were revealed at the protein level. Our study will have broader implications for understanding the mechanism of stem cell maintenance and fate determination and reversing the HSC aging process.

Synthesis, Characterization and Photophysical Properties of a New Family of Rare-earth Cluster-based Metal-organic Frameworks.

In this work, nine new rare-earth metal-organic frameworks (RE-MOFs, where RE = Lu(III), Yb(III), Tm(III), Er(III), Ho(III), Dy(III), Tb(III), Gd(III), and Eu(III)) isostructural to Zr-MOF-808 are synthesized, characterized, and studied regarding their photophysical properties. Materials with high crystallinity and surface area are obtained from a reproducible synthetic procedure that involves the use of two fluorinated modulators. At the same time, these new RE-MOFs display tunable photoluminescent properties due to efficient linker-to-metal energy transfer promoted by the antenna effect, resulting in a series of RE-MOFs displaying lanthanoid-based emissions spanning the visible and near-infrared regions of the electromagnetic spectrum.

Systemic gene therapy corrects neurological phenotype in a mouse model of NGLY1 deficiency.

The cytoplasmic peptide:N-glycanase (NGLY1) is ubiquitously expressed and functions as a de-N-glycosylating enzyme that degrades misfolded N-glycosylated proteins. NGLY1 deficiency due to biallelic loss-of-function NGLY1 variants is an ultrarare autosomal recessive deglycosylation disorder with multisystemic involvement; the neurological manifestations represent the major disease burden. Currently, there is no treatment for this disease. To develop a gene therapy, we first characterized a tamoxifen-inducible Ngly1 knock-out (iNgly1) C57BL/6J mouse model, which exhibited symptoms recapitulating human disease, including elevation of the biomarker GlcNAc-Asn (GNA), motor deficits, kyphosis, Purkinje cell loss, and gait abnormalities. We packaged a codon-optimized human NGLY1 transgene cassette into two adeno-associated virus (AAV) capsids, AAV9 and AAV.PHPeB. Systemic administration of the AAV.PHPeB vector to symptomatic iNgly1 mice corrected multiple disease features at eight weeks post-treatment. Furthermore, another cohort of AAV.PHPeB-treated iNgly1 mice were monitored over a year, and showed near-complete normalization of the neurological aspects of the disease phenotype, demonstrating the durability of gene therapy. Our data suggested that brain-directed NGLY1 gene replacement via systemic delivery is a promising therapeutic strategy for NGLY1 deficiency. Although the superior CNS tropism of AAV.PHPeB vector does not translate to primate, emerging AAV capsids with enhanced primate CNS tropism will enable future translational studies.

Relationship between adolescent internet addiction and adolescent non-suicidal self-injury: a moderated mediation model.

Background: Both Internet addiction (IA) and non-suicidal self-injury (NSSI) are major public health concerns among adolescents, association between internet addiction and non-suicidal self-injury have been observed among adolescents. However, it is unclear how, and under what conditions, internet addiction relates to non-suicidal self-injury. According to our hypothesis, there is a positive relationship between IA and NSSI among Chinese adolescents, but this relationship is affected by the mediating role of loneliness and the moderating role of cognitive reappraisal. Method: A cross-sectional survey was conducted on 1046 Chinese adolescents from 3 middle schools. Measurements: Adolescent Self-Harm Scale; Young's Internet Addiction Test (IAT); University of California at Los Angels (UCLA) Loneliness Scale; Emotional Regulation Questionnaire (ERQ), They were asked to complete self-report questionnaires. Results: In our sample, the detection rate of NSSI was 12.3%. IA was positively associated with NSSI, and loneliness partially mediated the association between them. In addition, cognitive reappraisal moderated the first half path of the mediation model. Specifically, the higher the level of cognitive reappraisal, the weaker the positive effect of IA on NSSI through loneliness. Conclusion: Interventions targeted to reduce loneliness and increase cognitive reappraisal strategies may reduce the risk of NSSI in adolescents with Internet addiction.

Critical Care Experience Shapes Respiratory Therapists' Attitudes toward Death: A Survey Study.

Respiratory therapists (RTs) frequently encounter death in their work with critically ill patients. Healthcare providers' attitudes toward death significantly affect their approach to caring for dying patients; however, there is a lack of knowledge on RTs' attitudes toward death. This study examines how the work environment and personal characteristics of RTs influence their attitudes toward death. Utilizing the Death Attitude Profile-Revised-Chinese questionnaire, a cross-sectional survey compared non-critical care RTs (non-CCRTs, N = 86) to critical care RTs (CCRTs, N = 85). Non-CCRTs displayed significantly lower scores in overall acceptance of death compared to CCRTs (p = 0.015) and a tendency to actively avoid thoughts about death (p = 0.005). CCRTs scored higher in "neutral acceptance" (p = 0.015), and non-CCRTs exhibited higher scores on items reflecting a negative attitude toward death. RTs with shorter professional tenures showed heightened fear of death and avoidance tendencies. Perception of life and death education correlated with higher "fear of death" and "death avoidance" scores (p = 0.001). The findings indicate that CCRTs demonstrate a more neutral acceptance of death. Additionally, experience, sex, mental health status, and life-death education exposure significantly influence RTs' attitudes toward death.

Optimizing Distributions for Associated Entropic Vectors via Generative Convolutional Neural Networks.

The complete characterization of the almost-entropic region yields rate regions for network coding problems. However, this characterization is difficult and open. In this paper, we propose a novel algorithm to determine whether an arbitrary vector in the entropy space is entropic or not, by parameterizing and generating probability mass functions by neural networks. Given a target vector, the algorithm minimizes the normalized distance between the target vector and the generated entropic vector by training the neural network. The algorithm reveals the entropic nature of the target vector, and obtains the underlying distribution, accordingly. The proposed algorithm was further implemented with convolutional neural networks, which naturally fit the structure of joint probability mass functions, and accelerate the algorithm with GPUs. Empirical results demonstrate improved normalized distances and convergence performances compared with prior works. We also conducted optimizations of the Ingleton score and Ingleton violation index, where a new lower bound of the Ingleton violation index was obtained. An inner bound of the almost-entropic region with four random variables was constructed with the proposed method, presenting the current best inner bound measured by the volume ratio. The potential of a computer-aided approach to construct achievable schemes for network coding problems using the proposed method is discussed.

Improved Anti-Oxidant and Anti-Bacterial Capacities of Skim Milk Fermented by Lactobacillus plantarum.

Milk, on account of its abundant protein content, is recognized as a vital source of bioactive substances. In this study, the bioactive ingredients in milk were obtained by a combination of protease hydrolysis and fermentation with Lactobacillus plantarum. The compositions of protease hydrolysate (PM) and fermentation supernatant (FM) were determined, and their anti-oxidant and anti-bacterial activities were evaluated. Using LC-MS/MS, the molecular weights and sequences of the peptides were characterized, among which a total of 25 bioactive peptides were identified. The DPPH radical scavenging results demonstrated that FM exhibited an enhanced anti-oxidant capacity compared to PM. The bacterial survival rate results revealed that FM had a remarkable anti-bacterial ability compared to PM. Additionally, the anti-bacterial component and potential anti-bacterial mechanisms were determined. The results of cytoplasmic membrane depolarization, cell membrane permeability, and morphological observation indicated that FM could interact with bacterial membranes to achieve its anti-bacterial effect. These findings suggested that FM, as a bioactive substance of natural origin, holds potential applications in the functional food, pharmaceutical, and cosmetic industries.

Breathable, Adhesive, and Biomimetic Skin-Like Super Tattoo.

Electronic tattoo, capable of imperceivably acquiring bio-electrical signals from the body, is broadly applied in healthcare and human-machine interface. Tattoo substrate, the foundation of electronic tattoo, is expected to be mechanically mimetic to skin, adhesive, and breathable, and yet remains highly challenging to achieve. Herein, the study mimics human skin and design a breathable, adhesive, and mechanically skin-like super tattoo substrate based on an ultra-thin film (≈2 µm). Similar to skin, super tattoo demonstrates strain-adaptive stiffening properties with high tear energy (5.4 kJ·m-2) and toughness (1.3 MJ·m-3). Superior to skin, it exhibits high adhesion, ionic conductivity, and permeability. A variety of conductive electrodes can be processed on it, showing the universality toward an ideal platform for electronic tattoo with stable and low contact impedance. Super tattoo-based electrodes can imperceivably and accurately monitor weak electromyography (EMG) of swallowing on the junction, providing effective guidance for rehabilitation training of dysphagia.

BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer.

The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.

Self-assembled superstructure alleviates air-water interface effect in cryo-EM.

Cryo-electron microscopy (cryo-EM) has been widely used to reveal the structures of proteins at atomic resolution. One key challenge is that almost all proteins are predominantly adsorbed to the air-water interface during standard cryo-EM specimen preparation. The interaction of proteins with air-water interface will significantly impede the success of reconstruction and achievable resolution. Here, we highlight the critical role of impenetrable surfactant monolayers in passivating the air-water interface problems, and develop a robust effective method for high-resolution cryo-EM analysis, by using the superstructure GSAMs which comprises surfactant self-assembled monolayers (SAMs) and graphene membrane. The GSAMs works well in enriching the orientations and improving particle utilization ratio of multiple proteins, facilitating the 3.3-Å resolution reconstruction of a 100-kDa protein complex (ACE2-RBD), which shows strong preferential orientation using traditional specimen preparation protocol. Additionally, we demonstrate that GSAMs enables the successful determinations of small proteins (<100 kDa) at near-atomic resolution. This study expands the understanding of SAMs and provides a key to better control the interaction of protein with air-water interface.

A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia.

Current medical therapies for treating acute myeloid leukemia (AML) remain unmet, and AML patients may benefit from targeted immunotherapy approaches that focus on specific tumor antigens. GRP78, which is upregulated in various malignant tumors such as AML, is partially expressed as cell surface GRP78 (csGRP78) on the cell membrane, making it an ideal target for redirecting T cells, including T-cell engagers. However, considering the conventional approach of using two scFv segments to construct a bispecific T-cell engager (BiTE), we have undertaken the development of a novel BiTE that utilizes a cyclic peptide ligand to specifically target csGRP78, which we refer to as GRP78-CD3/BiTE. We studied the effects of GRP78-CD3/BiTE on treatments for AML in vitro and in vivo and assessed the pharmacokinetics of this engager. Our findings demonstrated that GRP78-CD3/BiTE could not only effectively mediate the cytotoxicity of T cells against csGRP78-expressing AML cells but also specifically eliminate primary AML tumor cells in vitro. Furthermore, GRP78-CD3/BiTE exhibited a longer half-life despite having a lower molecular weight than CD19-CD3/BiTE. In a xenograft mouse model of AML, treatment with GRP78-CD3/BiTE prolonged the survival time of the mice. Our findings demonstrate that GRP78-CD3/BiTE is effective and selective for eliminating csGRP78-expressing AML cells and suggest that this approach to targeted immunotherapy could lead to effective new treatments for AML.

Single-Incision Laparoscopic Totally Extraperitoneal Sublay Repair of Lumbar Hernia: A Novel Technique.

Background: Lumbar hernia is a rare disease with low incidence, and no golden standard surgical procedure has been established for lumbar hernias. The single-incision laparoscopic totally extraperitoneal sublay (SIL-TES) technique became a novel surgical technique for lumbar hernias. Methods: This retrospective study included 20 patients who underwent SIL-TES repair for lumbar hernia between April 2020 and March 2024. The baseline patient characteristics, intraoperative data, postoperative data, satisfaction score, and Carolina Comfort Scale scores were collected. Results: The results revealed that the SIL-TES technique for lumbar hernia repair is associated with a low complication rate, nonrecurrence, high satisfaction score, and high quality of life after surgery. Conclusions: The SIL-TES technique could be a feasible and effective surgical technique for lumbar hernias. A controlled study is needed for further confirmation.

Coronary angiography was used to assess the effect of diabetes on off-pump coronary artery bypass graft patency.

This study aimed to examine the influence of diabetes on the left internal mammary artery (LIMA) and saphenous vein (SV) graft failure for 5-year follow-up. We enrolled 202 patients who underwent isolated off-pump coronary artery bypass grafting (CABG) surgery in 2014, angiographic follow-up occurred at 5 years after surgery. Angiographic outcomes in patients with or without diabetes were analyzed. Multivariate logistic regression analysis was used to identify independent predictors of graft dysfunction. A total of 66 (32.7%) patients had diabetes. Five-year rates of LIMA and SV graft failure were similar in patients with and without diabetes. In addition, in diabetics, the proportion of complete graft failure was significantly lower in the LIMA grafts (12/66, 18.2%) than in the SV grafts (57/133, 42.9%) (P = .001). In nondiabetic, the proportion of complete graft failure was also significantly lower in the LIMA grafts (28/136, 20.6%) than in the SV grafts (105/275, 38.2%) (P < .001). Multivariate logistic regression analysis showed that mean graft flow (MGF) was an independent predictor factor for LIMA (odds ratio = 1.186, 95% CI = 1.114-1.263, P < .001) and SV (odds ratio = 1.056, 95% CI = 1.035-1.077, P < .001) graft failure. Diabetes did not influence the patency of LIMA or SV grafts over a 5-year follow-up. LIMA grafts should be maximized in patients undergoing off-pump CABG surgery. Diabetes does not affect the patency of grafts CABG. Using angiography, our study proved that diabetes does not affect the patency of grafted vessels after CABG for 5 years.

The Identification of Potential Anti-Depression/Anxiety Drug Targets by Stress-Induced Rat Brain Regional Proteome and Network Analyses.

Depression and anxiety disorders are prevalent stress-related neuropsychiatric disorders and involve multiple molecular changes and dysfunctions across various brain regions. However, the specific and shared pathophysiological mechanisms occurring in these regions remain unclear. Previous research used a rat model of chronic mild stress (CMS) to segregate and identify depression-susceptible, anxiety-susceptible, and insusceptible groups; then the proteomes of six distinct brain regions (the hippocampus, prefrontal cortex, hypothalamus, pituitary, olfactory bulb, and striatum) were separately and quantitatively analyzed. To gain a comprehensive and systematic understanding of the molecular abnormalities, this study aimed to investigate and compare differential proteomics data from the six regions. Differentially expressed proteins (DEPs) were identified in between specific regions and across all regions and subjected to a series of bioinformatics analyses. Regional comparisons showed that stress-induced proteomic changes and corresponding gene ontology and pathway enrichments were largely distinct, attributable to differences in cell populations, protein compositions, and brain functions of these areas. Additionally, a notable degree of overlap in the significantly enriched terms was identified, potentially suggesting strong connections in the enrichment across different regions. Furthermore, intra-regional and inter-regional protein-protein interaction networks and drug-target-DEP networks were constructed. Integrated analysis of the three association networks in the six regions, along with the DisGeNET database, identified ten DEPs as potential targets for anti-depression/anxiety drugs. Collectively, these findings revealed commonalities and differences across different brain regions at the protein level induced by CMS, and identified several novel protein targets for the development of new therapeutics for depression and anxiety.

Disparities in clinical studies of AI enabled applications from a global perspective.

Artificial intelligence (AI) has been extensively researched in medicine, but its practical application remains limited. Meanwhile, there are various disparities in existing AI-enabled clinical studies, which pose a challenge to global health equity. In this study, we conducted an in-depth analysis of the geo-economic distribution of 159 AI-enabled clinical studies, as well as the gender disparities among these studies. We aim to reveal these disparities from a global literature perspective, thus highlighting the need for equitable access to medical AI technologies.

Variable importance analysis with interpretable machine learning for fair risk prediction.

Machine learning (ML) methods are increasingly used to assess variable importance, but such black box models lack stability when limited in sample sizes, and do not formally indicate non-important factors. The Shapley variable importance cloud (ShapleyVIC) addresses these limitations by assessing variable importance from an ensemble of regression models, which enhances robustness while maintaining interpretability, and estimates uncertainty of overall importance to formally test its significance. In a clinical study, ShapleyVIC reasonably identified important variables when the random forest and XGBoost failed to, and generally reproduced the findings from smaller subsamples (n = 2500 and 500) when statistical power of the logistic regression became attenuated. Moreover, ShapleyVIC reasonably estimated non-significant importance of race to justify its exclusion from the final prediction model, as opposed to the race-dependent model from the conventional stepwise model building. Hence, ShapleyVIC is robust and interpretable for variable importance assessment, with potential contribution to fairer clinical risk prediction.