A Non-canonical PDK1-RSK Signal Diminishes Pro-caspase-8-Mediated Necroptosis Blockade.

Necroptosis induction in vitro often requires caspase-8 (Casp8) inhibition by zVAD because pro-Casp8 cleaves RIP1 to disintegrate the necrosome. It has been unclear how the Casp8 blockade of necroptosis is eliminated naturally. Here, we show that pro-Casp8 within the necrosome can be inactivated by phosphorylation at Thr265 (pC8T265). pC8T265 occurs in vitro in various necroptotic cells and in the cecum of TNF-treated mice. p90 RSK is the kinase of pro-Casp8. It is activated by a mechanism that does not need ERK but PDK1, which is recruited to the RIP1-RIP3-MLKL-containing necrosome. Phosphorylation of pro-Casp8 at Thr265 can substitute for zVAD to permit necroptosis in vitro. pC8T265 mimic T265E knockin mice are embryonic lethal due to unconstrained necroptosis, and the pharmaceutical inhibition of RSK-mediated pC8T265 diminishes TNF-induced cecum damage and lethality in mice by halting necroptosis. Thus, phosphorylation of pro-Casp8 at Thr265 by RSK is an intrinsic mechanism for passing the Casp8 checkpoint of necroptosis.

Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS.

High levels of mitochondrial reactive oxygen species (mROS) are linked to cancer development, which is tightly controlled by the electron transport chain (ETC). However, the epigenetic mechanisms governing ETC gene transcription to drive mROS production and cancer cell growth remain to be fully characterized. Here, we report that protein demethylase PHF8 is overexpressed in many types of cancers, including colon and lung cancer, and is negatively correlated with ETC gene expression. While it is well known to demethylate histones to activate transcription, PHF8 demethylates transcription factor YY1, functioning as a co-repressor for a large set of nuclear-coded ETC genes to drive mROS production and cancer development. In addition to genetically ablating PHF8, pharmacologically targeting PHF8 with a specific chemical inhibitor, iPHF8, is potent in regulating YY1 methylation, ETC gene transcription, mROS production, and cell growth in colon and lung cancer cells. iPHF8 exhibits potency and safety in suppressing tumor growth in cell-line- and patient-derived xenografts in vivo. Our data uncover a key epigenetic mechanism underlying ETC gene transcriptional regulation, demonstrating that targeting the PHF8/YY1 axis has great potential to treat cancers.

Revisiting drug-protein interaction prediction: a novel global-local perspective.

MOTIVATION: Accurate inference of potential drug-protein interactions (DPIs) aids in understanding drug mechanisms and developing novel treatments. Existing deep learning models, however, struggle with accurate node representation in DPI prediction, limiting their performance. RESULTS: We propose a new computational framework that integrates global and local features of nodes in the drug-protein bipartite graph for efficient DPI inference. Initially, we employ pre-trained models to acquire fundamental knowledge of drugs and proteins and to determine their initial features. Subsequently, the MinHash and HyperLogLog algorithms are utilized to estimate the similarity and set cardinality between drug and protein subgraphs, serving as their local features. Then, an energy-constrained diffusion mechanism is integrated into the transformer architecture, capturing interdependencies between nodes in the drug-protein bipartite graph and extracting their global features. Finally, we fuse the local and global features of nodes and employ multilayer perceptrons to predict the likelihood of potential DPIs. A comprehensive and precise node representation guarantees efficient prediction of unknown DPIs by the model. Various experiments validate the accuracy and reliability of our model, with molecular docking results revealing its capability to identify potential DPIs not present in existing databases. This approach is expected to offer valuable insights for furthering drug repurposing and personalized medicine research. AVAILABILITY AND IMPLEMENTATION: Our code and data are accessible at: https://github.com/ZZCrazy00/DPI.

Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

Global research landscape on the contribution of de novo mutations to human genetic diseases over the past 20 years: bibliometric analysis.

As the contribution of de novo mutations (DNMs) to human genetic diseases has been gradually uncovered, analyzing the global research landscape over the past 20 years is essential. Because of the large and rapidly increasing number of publications in this field, understanding the current landscape of the contribution of DNMs in the human genome to genetic diseases remains a challenge. Bibliometric analysis provides an approach for visualizing these studies using information in published records in a specific field. This study aimed to illustrate the current global research status and explore trends in the field of DNMs underlying genetic diseases. Bibliometric analyses were performed using the Bibliometrix Package based on the R language version 4.1.3 and CiteSpace version 6.1.R2 software for publications from 2000 to 2021 indexed under the Web of Science Core Collection (WoSCC) about DNMs underlying genetic diseases on 17 September 2022. We identified 3435 records, which were published in 731 journals by 26,538 authors from 6052 institutes in 66 countries. There was an upward trend in the number of publications since 2013. The USA, China, and Germany contributed the majority of the records included. The University of Washington, Columbia University, and Baylor College of Medicine were the top-producing institutions. Evan E Eichler of the University of Washington, Stephan J Sanders of the Yale University School of Medicine, and Ingrid E Scheffer of the University of Melbourne were the most high-ranked authors. Keyword co-occurrence analysis suggested that DNMs in neurodevelopmental disorders and intellectual disabilities were research hotspots and trends. In conclusion, our data show that DNMs have a significant effect on human genetic diseases, with a noticeable increase in annual publications over the last 5 years. Furthermore, potential hotspots are shifting toward understanding the causative role and clinical interpretation of newly identified or low-frequency DNMs observed in patients.

An Effective Plant Small Secretory Peptide Recognition Model Based on Feature Correction Strategy.

Plant small secretory peptides (SSPs) play an important role in the regulation of biological processes in plants. Accurately predicting SSPs enables efficient exploration of their functions. Traditional experimental verification methods are very reliable and accurate, but they require expensive equipment and a lot of time. The method of machine learning speeds up the prediction process of SSPs, but the instability of feature extraction will also lead to further limitations of this type of method. Therefore, this paper proposes a new feature-correction-based model for SSP recognition in plants, abbreviated as SE-SSP. The model mainly includes the following three advantages: First, the use of transformer encoders can better reveal implicit features. Second, design a feature correction module suitable for sequences, named 2-D SENET, to adaptively adjust the features to obtain a more robust feature representation. Third, stack multiple linear modules to further dig out the deep information on the sample. At the same time, the training based on a contrastive learning strategy can alleviate the problem of sparse samples. We construct experiments on publicly available data sets, and the results verify that our model shows an excellent performance. The proposed model can be used as a convenient and effective SSP prediction tool in the future. Our data and code are publicly available at https://github.com/wrab12/SE-SSP/.

Ligand effect on Ru-centered species toward methane activation.

Ligands have been known to profoundly affect the chemical transformations of methane, yet significant challenges remain in shedding light on the underlying mechanisms. Here, we demonstrate that the conversion of methane can be regulated by Ru centered cations with a series of ligands (C, CH, CNH, CHCNH). Gas-phase experiments complemented by theoretical dynamic analysis were performed to explore the essences and principles governing the ligand effect. In contrast to the inert Ru+, [RuC]+, and [RuCNH]+ toward CH4, the dehydrogenation dominates the reaction of ligand-regulated systems [RuCH]+/CH4 and [RuCHCNH]+/CH4. In active cases, CH acts as active sites, and regulates the activation of CH4 assisted by the "seemingly inert" CNH ligand.

Carbon-Atom Exchange between [MC2]+ (M = Os and Ir) and Methane: on the Thermodynamic and Dynamic Aspects.

Gas-phase reactions of [OsC2]+ and [IrC2]+ with methane at ambient temperature have been studied using quadrupole-ion trap mass spectrometry combined with quantum chemical calculations. Both [OsC2]+ and [IrC2]+ undergo carbon-atom exchange reactions with methane. The associated mechanisms for the two systems are found to be similar. The differences in the rates of carbon isotope exchange reactions of methane with [MC2]+ (M = Os and Ir) are explained by several factors like the energy barrier for the initial H3C-H bond breaking processes, the molecular dynamics, orbital interactions, and the H-binding energies of the pivotal steps. Besides, the number of participating valence orbitals might be one of the keys to regulate the rate in the key step. The present findings may provide useful ideas and inspiration for designing similar processes.

Nonlinear differential equations and their application to evaluating the integrated impacts of multiple parameters on the biochemical safety of drinking water.

The present study aimed to narrow such gaps by applying nonlinear differential equations to biostability in drinking water. Biostability results from the integrated dynamics of nutrients and disinfectants. The linear dynamics of biostability have been well studied, while there remain knowledge gaps concerning nonlinear effects. The nonlinear effects are explained by phase plots for specific scenarios in a drinking water system, including continuous nutrient release, flush exchange with the adjacent environment, periodic pulse disinfection, and periodic biofilm development. The main conclusions are, (1) The correlations between the microbial community and nutrients go through phases of linear, nonlinear, and chaotic dynamics. Disinfection breaks the chaotic phase and returns the system to the linear phase, increasing the microbial growth potential. (2) Post-disinfection after multiple microbial peaks produced via metabolism can increase disinfection efficiency and decrease the risks associated with disinfectant byproduct risks. This can provide guidelines for optimizing the disinfection strategy, according to the long-term water safety target or a short management. Limited disinfection and ultimate disinfection may be more effective and have low chemical risk, facing longer stagnant conditions. (3) Periodic biofilm formation and biofilm detachment increase the possibility of uncertainty in the chaotic phase. For future study, nonlinear differential equation models can accordingly be applied at the molecular and ecological levels to further explore more nonlinear regulation mechanisms.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis.

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care. Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed. Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens. Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

On the performance of the M-C (M = Fe, Ru, Os) unit toward methane activation.

Gas-phase reactions of [MC]+ (M = Os and Ru) with methane at ambient temperature have been studied by using quadrupole-ion trap (Q-IT) mass spectrometry combined with quantum chemical calculations. Theoretical calculations reveal the influence of electronic signatures and that it is the energy gap of the associated frontier molecular orbitals that dominates the ability of the cluster in the initial H3C-H bond breaking. By extension, a theoretical consideration upon changing the ligand from carbide to carbyne and eventually to carbene reveals that the reactivities of the M-complex (M = Os, Ru and Fe) are determined by the energy gap of the involved orbitals. In addition, a few factors like the dipole moment, spin density and charge distributions influence the orbital energy gap to different extents. Thus, altering the local structure of the active center to modulate the orbital distribution may be a possible means of regulation of the activity.

Systematic Review of Published Cases of Primary Epithelioid Sarcoma of the Spine.

BACKGROUND Epithelioid sarcoma is rare, represents less than 1% of all sarcomas, usually occurs in the extremities, and rarely presents as a primary sarcoma of the spine. Publications are usually single reports or case series. We aimed to undertake a systematic review of publications of cases of primary epithelioid sarcoma of the spine to evaluate clinical presentation, diagnosis, management, and patient outcomes. MATERIAL AND METHODS We searched studies on spinal epithelioid sarcoma in the PubMed database. Only studies with secondary epithelioid sarcoma or without effective data for analysis were excluded. Cases in which epithelioid sarcoma first invaded other sites and then affected the spine were also excluded. RESULTS Twenty-three patients from 13 studies were included in the study, aged between 14 and 65 years, and the sex ratio of female to male was 1: 2.29. The survival time was 18.7±13.8 months. The survival time of males was longer than that of females (22.9±14.4 vs 9.0±4.6, P=0.027). The onset age was linearly correlated with the size of the lesion (size=-0.161*age+11.841).The lesions located in lumbar vertebra had the worst prognosis. Postoperative radiotherapy had a statistically significant effect on survival time (P=0.040). CONCLUSIONS This systematic review identified 23 published cases of primary epithelioid sarcoma of the spine. Pain was the main presenting symptom, and tumor size increased with patient age. Female sex and primary location in the lumbar spine were associated with poor survival. Although surgery was the first-line treatment, postoperative radiotherapy and chemotherapy may improve clinical outcomes.

Effects of different modes of exercise on skeletal muscle mass and function and IGF-1 signaling during early aging in mice.

Skeletal muscle mass and function tend to decline with increasing age. Insulin-like growth factor 1 (IGF-1) plays a key role in promoting skeletal muscle growth. Exercise improves skeletal muscle mass and function via the activation of IGF-1 signaling. The aim of this study was to investigate whether different types of exercise can promote muscle hypertrophy, exercise and metabolic capacities, and activate IGF-1 signaling during early aging in mice. We randomly assigned 12 month old male C57/BL6 mice into five groups: control, aerobic exercise, resistance exercise, whole-body vibration and electrical stimulation group. Gastrocnemius muscle mass, myofiber size, levels of IGF-1 signaling, oxidative stress, protein synthesis and degradation, and apoptosis were detected. C2C12 cells were used to explore the mechanism by which exercise exerts its effects. We confirmed that the four modes of exercise increased skeletal muscle mass, exercise capacity, indicators of metabolism and protein synthesis, and inhibited oxidative stress and apoptosis via activation of the IGF-1 pathway. The most effective intervention was resistance exercise. Whole-body vibration promoted muscle hypertrophy better than aerobic exercise. Furthermore, in the in vitro experiment, the importance of IGF-1/IGF-1R-PI3K/Akt signaling for maintaining skeletal muscle mass was confirmed. Aerobic exercise, resistance exercise, whole-body vibration and electrical stimulation increased skeletal muscle mass, exercise capacity, protein synthesis and metabolic enzyme activity, and inhibited protein degradation and apoptosis in mice undergoing early aging via activation of IGF-1 signaling. Of these, whole-body vibration has been shown to be significantly effective and is similar to conventional exercise in promoting muscle hypertrophy.

Iridium Dimer Anion-Mediated C≡C Triple Bond Cleavage and Successive Dehydrogenation of Acetylene in the Gas Phase.

The reactions of the iridium dimer anion [Ir2]- with acetylene have been studied by mass spectrometry in the gas phase, which indicate that the [Ir2]- anion can consecutively react with C2H2 molecules to form the [Ir2C2x]- (x = 1, 2) and [Ir2C2yH2]- (y = 3-5) anions as major products with the successive release of H2 molecules at room temperature. The reactions are confirmed by the reactions of the mass-selected product [Ir2C2]- anion with C2H2 to produce [Ir2C4]- and [Ir2C2yH2]- (y = 3-5). Photoelectron spectra and quantum chemistry calculations confirm that the [Ir2C2x]- (x = 1, 2) product anions possess cyclic [Ir(µ-C)2Ir]- and [Ir(µ-C)(µ-C3)Ir]- structures, implying that the robust C≡C triple bond of acetylene can be completely cleaved by the [Ir2]- anion.

The Adhesive Perinephric Fat Score is Correlated with Outcomes of Retroperitoneal Laparoscopic Adrenalectomy for Benign Diseases.

BACKGROUND: Retroperitoneal laparoscopic adrenalectomy (RLA) possessing unique superiority with minimal abdominal interference is complicated by the status of periadrenal fat, including its quantity and texture. We hypothesized that an adherent perinephric fat predictor, the Mayo Adhesive Probability score (Mayo score), is associated with the perioperative outcomes of RLA. METHODS: This retrospective study included consecutive patients who underwent RLA for the diagnosis of benign adrenal tumors at our institution between 2017 and 2020. Medical records were reviewed to evaluate the association between Mayo scores obtained from preoperative computed tomography imaging and surgical outcomes as well as complications. Factors independently related to perioperative results were analyzed using multivariable regression models. RESULTS: In total, 186 RLA were included. According to their Mayo scores, the patients were divided as follows: 0 (n = 51, 27.4%), 1 (n = 34, 18.3%), 2 (n = 45, 24.2%), 3 (n = 29, 15.6%), 4 (n = 16, 8.6%) and 5 (n = 11, 5.9%). Longer operative time (92.0 ± 25.0 vs. 114.7 ± 30.6 vs. 137.4 ± 27.1 min, P < 0.001), higher estimated blood loss (42.2 ± 28.1 vs. 70.5 ± 44.9 vs. 132.6 ± 63.4 mL, P < 0.001) and greater decline of hemoglobin (0.7 ± 0.4 vs. 1.0 ± 0.4 vs. 1.3 ± 0.6 g/dL, P < 0.001) were significantly associated with elevated Mayo score risks. No difference in complication rates was found. The score was identified as a unique, independent risk factor for perioperative outcomes on multivariable analysis. CONCLUSIONS: The Mayo score is a vital outcome predictor of RLA. It may be utilized in the preoperative planning for patients undergoing RLA.

The Reactive Sites of Methane Activation: A Comparison of IrC3+ with PtC3.

The activation reactions of methane mediated by metal carbide ions MC3+ (M = Ir and Pt) were comparatively studied at room temperature using the techniques of mass spectrometry in conjunction with theoretical calculations. MC3+ (M = Ir and Pt) ions reacted with CH4 at room temperature forming MC2H2+/C2H2 and MC4H2+/H2 as the major products for both systems. Besides that, PtC3+ could abstract a hydrogen atom from CH4 to generate PtC3H+/CH3, while IrC3+ could not. Quantum chemical calculations showed that the MC3+ (M = Ir and Pt) ions have a linear M-C-C-C structure. The first C-H activation took place on the Ir atom for IrC3+. The terminal carbon atom was the reactive site for the first C-H bond activation of PtC3+, which was beneficial to generate PtC3H+/CH3. The orbitals of the different metal influence the selection of the reactive sites for methane activation, which results in the different reaction channels. This study investigates the molecular-level mechanisms of the reactive sites of methane activation.

The Geriatric Nutritional Risk Index Predicts Overall Survival in Geriatric Patients with Metastatic Lung Adenocarcinoma.

The geriatric nutritional risk index (GNRI) is a simplified nutritional assessment. This study aimed to evaluate the prognostic value of the pretreatment GNRI in geriatric patients with metastatic lung adenocarcinoma (MLA). The clinicopathological characteristics of 144 geriatric patients with MLA were analyzed. The receiver operating characteristic curve was used to determine the best cutoff value of GNRI for predicting overall survival (OS). The Cox regression was used to identify variables associated with OS in the whole group, the non-sensitizing EGFR mutation subgroup, and the sensitizing EGFR mutation subgroup. The best cutoff value of the GNRI was 97 and the incidence of malnutrition risk was 52.1%. Low GNRI were significantly associated with older age (p = 0.002), a high ECOG score (p = 0.037), and a high neutrophil/lymphocyte ratio (p = 0.004). Low GNRI (p < 0.001), liver metastases (p < 0.001), and EGFR mutations (p < 0.001) were independent prognostic factors of OS. Low GNRI (p = 0.001), liver metastases (p < 0.001), and a high ECOG score (p = 0.003) were independent prognostic factors of OS in the non-sensitizing EGFR mutation subgroup, but not in the sensitizing EGFR mutation subgroup. This study shows the importance of the GNRI in predicting OS in geriatric patients with MLA, especially in patients without sensitizing EGFR mutations.

Reactions of Transition-Metal Carbyne Cations with Ethylene in the Gas Phase.

The reactions of iridium- and osmium-carbyne hydride cations [HIrCH]+ and [HOsCH]+ with ethylene have been studied using mass spectrometry with isotopic-labeling in the gas phase. The carbyne reactivity is compared with that of the rhodium, cobalt, and iron analogues [TMCH2]+ (TM = Fe, Co, and Rh), which were determined to have the carbene structures. Besides the cycloaddition/dehydrogenation reaction in forming the [TMC3H4]+ + H2 (TM = Ir and Os) products, a second reaction pathway producing the [TMC2H2]+ ion and CH4 via triple hydrogen atom transfer reactions to the carbyne carbon is observed to be the major channel. The latter channel is not observed in the rhodium, cobalt, and iron carbene cation reactions. Quantum-chemical calculations indicate that the distinct reactivity is not due to different initial structures of the reactants. Both reaction channels are predicted to be thermodynamically exothermic and kinetically facile for the carbyne cations, and the reactions proceed with the initial formation of a carbene intermediate via hydride-carbyne coupling. The latter channel is also exothermic but kinetically unfavorable for the rhodium, cobalt, and iron carbene cations.

Single Atoms of Iron on MoS2 Nanosheets for N2 Electroreduction into Ammonia.

Efforts have been devoted to achieving a highly efficient artificial synthesis of ammonia (NH3 ). Reported herein is a novel Fe-MoS2 catalyst with Fe atomically dispersed onto MoS2 nanosheets, imitating natural nitrogenase, to boost N2 electroreduction into NH3 at room temperature. The Fe-MoS2 nanosheets exhibited a faradic efficiency of 18.8 % with a yield rate of 8.63 µg NH 3 mgcat. -1 h-1 for NH3 at -0.3 V versus the reversible hydrogen electrode. The mechanism study revealed that the electroreduction of N2 was promoted and the competing hydrogen evolution reaction was suppressed by decorating the edge sites of S in MoS2 with the atomically dispersed Fe, resulting in high catalytic performance for the electroreduction of N2 into NH3 . This work provides new ideas for the design of catalysts for N2 electroreduction and strengthens the understanding about N2 activation over Mo-based catalysts.