Initiation Factor Research Articles

Screen11: validating a screening instrument for voice disorders in accordance with the COSMIN framework

Purpose Although numerous patient-reported outcome measures have been developed and validated to quantify the impact of voice problems on different aspects of life, to our knowledge no screening instrument exists that specifically captures voice disorders in a retrospective fashion. The aim of the present study was to examine the psychometric properties and diagnostic validity of a retrospective voice screening method, Screen11, according to the COSMIN framework for health-related, patient-reported outcome measures. The items in Screen11 have been used to establish the prevalence of voice disorders in both general and occupation-specific populations in the Nordic countries. However, the instrument has not been validated. Methods The voice patient group (n = 54) in this study comprised of patients from the Turku University Central Hospital phoniatric outpatient clinic seeking help for their voice problems. For these voice patients, we recruited voice-healthy controls (n = 61) who matched in terms of gender, age, and occupation. The participants responded to the Screen11 questionnaire along with the VHI and the VAPP. Results The results of the initial exploratory factor analysis showed that all the Screen11 items loaded on a common underlying latent factor. Furthermore, Screen11 had high internal consistency (α = .93) and correlated sufficiently with other voice questionnaires. Conclusions The results indicate that Screen11, which screens for possible voice disorders at an early stage, was successfully validated. With respect to its diagnostic validity, the Screen11 sum score is preferable. A threshold of ≥ 15 should be used for differentiating patients with possible voice disorders from those with healthy voices.

Hesperetin blocks poxvirus replication with a low tendency to select for drug-resistant viral variants.

In this study, we demonstrated the antiviral efficacy of hesperetin against multiple poxviruses, including buffalopox virus (BPXV), vaccinia virus (VACV), and lumpy skin disease virus (LSDV). The time-of-addition and virus step-specific assays indicated that hesperetin reduces the levels of viral DNA, mRNA, and proteins in the target cells. Further, by immunoprecipitation (IP) of the viral RNA from BPXV-infected Vero cells and a cell-free RNA-IP assay, we demonstrated that hesperetin-induced reduction in BPXV protein synthesis is also consistent with diminished interaction between eukaryotic translation initiation factor eIF4E and the 5' cap of viral mRNA. Molecular docking and MD simulation studies were also consistent with the binding of hesperetin to the cap-binding pocket of eIF4E, adopting a conformation similar to m7GTP binding. Furthermore, in a BPXV egg infection model, hesperetin was shown to suppress the development of pock lesions on the chorioallantoic membrane and associated mortality in the chicken embryos. Most importantly, long-term culture of BPXV in the presence of hesperetin did not induce the generation of drug-resistant viral mutants. In conclusion, we, for the first time, demonstrated the antiviral activity of hesperetin against multiple poxviruses, besides providing some insights into its potential mechanisms of action.

Substrate recruitment via eIF2γ enhances catalytic efficiency of a holophosphatase that terminates the integrated stress response

Dephosphorylation of pSer51 of the α subunit of translation initiation factor 2 (eIF2αP) terminates signaling in the integrated stress response (ISR). A trimeric mammalian holophosphatase comprised of a protein phosphatase 1 (PP1) catalytic subunit, the conserved C-terminally located ~70 amino acid core of a substrate-specific regulatory subunit (PPP1R15A/GADD34 or PPP1R15B/CReP) and G-actin (an essential cofactor) efficiently dephosphorylate eIF2αP in vitro. Unlike their viral or invertebrate counterparts, with whom they share the conserved 70 residue core, the mammalian PPP1R15s are large proteins of more than 600 residues. Genetic and cellular observations point to a functional role for regions outside the conserved core of mammalian PPP1R15A in dephosphorylating its natural substrate, the eIF2 trimer. We have combined deep learning technology, all-atom molecular dynamics simulations, X-ray crystallography, and biochemistry to uncover binding of the γ subunit of eIF2 to a short helical peptide repeated four times in the functionally important N terminus of human PPP1R15A that extends past its conserved core. Binding entails insertion of Phe and Trp residues that project from one face of an α-helix formed by the conserved repeats of PPP1R15A into a hydrophobic groove exposed on the surface of eIF2γ in the eIF2 trimer. Replacing these conserved Phe and Trp residues with Ala compromises PPP1R15A function in cells and in vitro. These findings suggest mechanisms by which contacts between a distant subunit of eIF2 and elements of PPP1R15A distant to the holophosphatase active site contribute to dephosphorylation of eIF2αP by the core PPP1R15 holophosphatase and to efficient termination of the ISR in mammals.

Brief multidimensional self-control scale: psychometric properties and cross-gender measurement invariance of the Portuguese version

ABSTRACT Self-control has been traditionally defined as the capacity to inhibit or overrule immediate urges in order to attain long-term goals, and it is considered an important topic of research in criminology and forensic psychology. The aim of the present study is to examine the psychometric properties of the Portuguese version of the Brief Multidimensional Self-Control Scale (BMSCS). Our sample consisted of 242 male and female participants (M = 30.19 years, SD = 12.78, range = 16–77 years) from Portugal. The one-factor model and the two-factor second-order model obtained adequate fits. Internal consistency/reliability, as measured by the alpha and omega coefficients, was adequate when considering the BMSCS total but the Inhibition and Initiation factors tended to present lower values. Convergent validity (with other self-control measures), divergent validity, and criterion-related validity (with justice-involvement and alcohol/drug abuse variables) were demonstrated. Measurement invariance across gender was established, with no significant differences being found when comparing male and female participants. Our findings add novel information and mostly support the use of the recently developed BMSCS as a short, valid, and reliable measure of self-control.

Optical Transient Source AT2021lfa: A Possible “Dirty Fireball”

AT2021lfa, also known as ZTF21aayokph, was detected by the Zwicky Transient Facility on 2021 May 4, at 05:34:48 UTC. Follow-up observations were conducted using a range of ground-based optical telescopes, as well as Swift/XRT and VLA instruments. AT2021lfa is classified as an “orphan afterglow” candidate due to its rapid flux decline and its reddened color (g − r = 0.17 ± 0.14 mag). For an optical transient source without prompt gamma-ray detection, one key point is to determine its burst time. Here we measure the burst time through fitting the initial bump feature of AT2021lfa and obtain its burst time as 2021 May 3, at 22:09:50 UTC. Using afterglowpy, we model the multi-band afterglow of AT2021lfa and find that the standard model cannot reproduce the late radio observations well. Considering that the microphysical parameters ϵ e , ϵ B (the energy fraction given to electrons and magnetic field), and ξ N (the fraction of accelerated electrons) may vary with time, we then model the afterglow of AT2021lfa taking into account the temporal evolution of the physical parameters ϵ e , ϵ B , and ξ N and find in this case the multi-wavelength observations can be reproduced well. The initial Lorentz factor of AT2021lfa can be estimated from the peak time of the early afterglow, which yields a value of about 18, suggesting that AT2021lfa should be classified as a “dirty fireball.” From the upper limit for the prompt emission energy of AT2021lfa, we obtain that the radiation efficiency is less than 0.02%, which is much smaller than that of ordinary gamma-ray bursts (GRBs). It is also interesting that the fitted values of jet angle and viewing angle are very large, θ c ∼ 0.66 rad, θ v ∼ 0.53 rad, which may lead to the low Lorentz factor and radiation efficiency. When compared with GRB afterglow samples, it is evident that the onset bump timescale of AT2021lfa satisfies the empirical relationships observed in GRB samples. Additionally, the luminosity of AT2021lfa falls within the range of observations for GRB samples; however, approximately 1 day after the burst, its luminosity exceeds that of the majority of GRB samples.

Low-Density Lipoproteins Increase Proliferation, Invasion, and Chemoresistance via an Exosome Autocrine Mechanism in MDA-MB-231 Chemoresistant Cells.

Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic strategy; however, chemoresistance remains a significant challenge. Exosomes (Exs) secreted by tumoral cells have been implicated in cell communication pathways and chemoresistance mechanisms; the content of exosomes is an outcome of cellular cholesterol metabolism. We previously induced Dox resistance in TNBC cell models, characterizing a variant denominated as variant B cells. Our results suggest that LDL internalization in parental and chemoresistant variant B cells is associated with increased cell proliferation, migration, invasion, and spheroid growth. We identified the role of eIF4F translation initiation factor and the down-regulation of tumor suppressor gene PDCD4, an inhibitor of eIF4A, in chemoresistant variant B cells. In addition, the exomes secreted by variant B cells were characterized by the protein content, electronic microscopy, and cell internalization assays. Critically, exosomes purified from LDL-treated variant B cell promoted cell proliferation, migration, and an increment in lactate concentration. Our results suggest that an autocrine phenomenon induced by exosomes in chemoresistant cells may induce modifications on signaling mechanisms of the p53/Mdm2 axis and activation of p70 ribosomal protein kinase S6. Moreover, the specific down-regulated profile of chaperones Hsp90 and Hsp70 secretion inside the exosomes of the chemoresistant variant could be associated with this phenomenon. Therefore, autocrine activation mediated by exosomes and the effect of LDL internalization may influence changes in exosome chaperone content and modulate proliferative signaling pathways, increasing the aggressiveness of MDA-MB-231 chemoresistant cells.

Circ_0104652 Promotes the Proliferation and Migration of ox-LDL-Stimulated Vascular Smooth Muscle Cells via Stabilizing ADAMTS7 and HMGB1.

Atherosclerosis (AS) stands as the primary contributor to cardiovascular disease, a pervasive global health concern. Extensive research has underscored the pivotal role of circular RNAs (circRNAs) in cardiovascular disease development. However, the specific functions of numerous circRNAs in AS remain poorly understood. Quantitative real-time PCR analysis revealed a significant upregulation of circ_0104652 in oxidized low-density lipoprotein (ox-LDL)-induced vascular smooth muscle cells (VSMCs). Loss-of-function experiments were subsequently employed to assess the impact of circ_0104652 on ox-LDL-induced VSMCs. Silencing circ_0104652 was found to impede the proliferation and migration while promoting the apoptosis of ox-LDL-stimulated VSMCs. Mechanistic assays unveiled that circ_0104652 stabilized ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7) and high mobility group box 1 (HMGB1) by recruiting eukaryotic translation initiation factor 4A3 (EIF4A3) protein. Rescue assays further confirmed that circ_0104652 exerted its influence on ox-LDL-induced VSMC proliferation through modulation of ADAMTS7 and HMGB1. This study elucidates the role of the circ_0104652/EIF4A3/ADAMTS7/HMGB1 axis in ox-LDL-stimulated VSMCs, providing valuable insights into the intricate mechanisms involved.

Promoting the production of challenging proteins via induced expression in CHO cells and modified cell-free lysates harboring T7 RNA polymerase and mutant eIF2α

Chinese hamster ovary (CHO) cells are crucial in biopharmaceutical production due to their scalability and capacity for human-like post-translational modifications. However, toxic proteins and membrane proteins are often difficult-to-express in living cells. Alternatively, cell-free protein synthesis can be employed. This study explores innovative strategies for enhancing the production of challenging proteins through the modification of CHO cells by investigating both, cell-based and cell-free approaches. A major result in our study involves the integration of a mutant eIF2 translation initiation factor and T7 RNA polymerase into CHO cell lysates for cell-free protein synthesis. This resulted in elevated yields, while eliminating the necessity for exogenous additions during cell-free production, thereby substantially enhancing efficiency. Additionally, we explore the potential of the Rosa26 genomic site for the integration of T7 RNA polymerase and cell-based tetracycline-controlled protein expression. These findings provide promising advancements in bioproduction technologies, offering flexibility to switch between cell-free and cell-based protein production as needed.

Repeated exposure to eucalyptus wood smoke alters pulmonary gene and metabolic profiles in male Long-Evans rats.

Exposure to wildfire smoke is associated with both acute and chronic cardiopulmonary illnesses, which are of special concern for wildland firefighters who experience repeated exposure to wood smoke. It is necessary to better understand the underlying pathophysiology by which wood smoke exposure increases pulmonary disease burdens in this population. We hypothesize that wood smoke exposure produces pulmonary dysfunction, lung inflammation, and gene expression profiles associated with future pulmonary complications. Male Long-Evans rats were intermittently exposed to smoldering eucalyptus wood smoke at 2 concentrations, low (11.0 ± 1.89 mg/m3) and high (23.7 ± 0.077 mg/m3), over a 2-week period. Whole-body plethysmography was measured intermittently throughout. Lung tissue and lavage fluid were collected 24 h after the final exposure for transcriptomics and metabolomics. Increasing smoke exposure upregulated neutrophils and select cytokines in the bronchoalveolar lavage fluid. In total, 3446 genes were differentially expressed in the lungs of rats in the high smoke exposure and only 1 gene in the low smoke exposure (Cd151). Genes altered in the high smoke group reflected changes to the Eukaryotic Initiation Factor 2 stress and oxidative stress responses, which mirrored metabolomics analyses. xMWAS-integrated analysis revealed that smoke exposure significantly altered pathways associated with oxidative stress, lung morphogenesis, and tumor proliferation pathways. These results indicate that intermittent, 2-week exposure to eucalyptus wood smoke leads to transcriptomic and metabolic changes in the lung that may predict future lung disease development. Collectively, these findings provide insight into cellular signaling pathways that may contribute to the chronic pulmonary conditions observed in wildland firefighters.

A wave of specific transcript and protein accumulation accompanies pollen dehydration.

In flowering plants, male gametes are immotile and carried by dry pollen grains to the female organ. Dehydrated pollen is thought to withstand abiotic stress when grains are dispersed from the anther to the pistil, after which sperm cells are delivered via pollen tube growth for fertilization and seed set. Yet, the underlying molecular changes accompanying dehydration and the impact on pollen development are poorly understood. To gain a systems perspective, we analyzed published transcriptomes and proteomes of developing Arabidopsis thaliana pollen. Waves of transcripts are evident as microspores develop to bicellular, tricellular, and mature pollen. Between the 'early'- and 'late'-pollen-expressed genes, an unrecognized cluster of transcripts accumulated, including those encoding late-embryogenesis abundant (LEA), desiccation-related protein, transporters, lipid-droplet associated proteins, pectin modifiers, cysteine-rich proteins, and mRNA-binding proteins. Results suggest dehydration onset initiates after bicellular pollen is formed. Proteins accumulating in mature pollen like ribosomal proteins, initiation factors, and chaperones are likely components of mRNA-protein condensates resembling 'stress' granules. Our analysis has revealed many new transcripts and proteins that accompany dehydration in developing pollen. Together with published functional studies, our results point to multiple processes, including i) protect developing pollen from hyperosmotic stress, ii) remodel the endomembrane system and walls; iii) maintain energy metabolism, iv) stabilize pre-synthesized mRNA and proteins in condensates of dry pollen, and v) equip pollen for compatibility determination at the stigma and for recovery at rehydration. These findings offer novel models and molecular candidates to further determine the mechanistic basis of dehydration and desiccation tolerance in plants.

Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in Dextran Sulfate Sodium-Induced Murine Model of Ulcerative Colitis.

Oxidative stress is implicated in the pathogenesis of various acute disorders including ischemia/reperfusion injury, ultraviolet/radiation burn, as well as chronic disorders such as dyslipidemia, atherosclerosis, diabetes mellitus, chronic renal disease, and inflammatory bowel disease (IBD). However, the precise mechanism involved remains to be clarified. We formerly identified a novel apoptosis-inducing humoral protein, in a hypoxia/reoxygenation-conditioned medium of cardiac myocytes, which proved to be 69th tyrosine-sulfated eukaryotic translation initiation factor 5A (eIF5A). We named this novel tyrosine-sulfated secreted form of eIF5A Oxidative Stress-Responsive Apoptosis-Inducing Protein (ORAIP). To investigate the role of ORAIP in a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis (UC), we analyzed the effects of in vivo treatment with anti-ORAIP neutralizing monoclonal antibody (mAb) on the DSS-induced disease exacerbation. The body weight in anti-ORAIP mAb-treated group was significantly heavier than that in a mouse IgG-treated control group on day 8 of DSS-treatment ((85.21 ± 1.03%) vs. (77.38 ± 2.07%); (mean ± SE0, n = 5 each, p < 0.01, t-test). In vivo anti-ORAIP mAb-treatment also significantly suppressed the shortening of colon length as well as Disease Activity Index (DAI) score ((5.00 ± 0.44) vs. (8.20 ± 0.37); (mean ± SE), n = 5 each, p < 0.001, t-test) by suppressing inflammation of the rectal tissue and apoptosis of intestinal mucosal cells. These data reveal the pivotal role of ORAIP in DSS-induced oxidative stress involved in an animal model of UC.

Social defeat stress induces liver injury by modulating endoplasmic reticulum stress in C57BL/6J mice

Social defeat stress is associated with endoplasmic reticulum (ER) stress, inflammation and apoptosis. ER stress is thought to contribute to many lifestyle diseases such as liver injury, cardiovascular dysfunction and depression. We investigated the expression of the ER stress markers RNA-dependent protein kinase-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α) and C/EBP homologous protein (CHOP), as well as inflammatory and apoptotic factors, to assess how social defeat stress induces liver injury. Furthermore, we evaluated the effects of the ER stress inhibitor phenylbutyric acid (PBA) and ER stress inducer thapsigargin (TG) on liver injury. Adult mice were divided into the control, social defeat, social defeat + PBA, TG, PBA and TG + PBA groups. The social defeat and social defeat + PBA groups were simultaneously exposed to social defeat stress for 10 days. The social defeat + PBA, TG, PBA and TG + PBA groups were treated with PBA or TG via intraperitoneal injections. PBA was injected 1 h before the TG injection into the TG + PBA group. Liver samples from six groups of mice were analyzed by histological analysis and western blotting. Social defeat stress promoted ER stress, increased the expression of inflammatory factors and induced apoptosis in the liver of socially defeated mice, which was reversed by PBA. Moreover, ER stress induces TG-induced liver injury by initiating ER stress. Social defeat stress initiates ER stress, promotes the expression of inflammatory and apoptotic factors, and induces liver injury. PBA suppresses liver injury caused by social defeat stress and TG treatment.

Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators.

The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC50=67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.

Endoplasmic reticulum stress response in immune cells contributes to experimental autoimmune encephalomyelitis pathogenesis in rats

We examined the role of endoplasmic reticulum (ER) stress and the ensuing unfolded protein response (UPR) in the development of the central nervous system (CNS)-directed immune response in the rat model of experimental autoimmune encephalomyelitis (EAE). The induction of EAE with syngeneic spinal cord homogenate in complete Freund's adjuvant (CFA) caused a time-dependent increase in the expression of ER stress/UPR markers glucose-regulated protein 78 (GRP78), X-box-binding protein 1 (XBP1), C/EBP homologous protein (CHOP), and phosphorylated eukaryotic initiation factor 2α (eIF2α) in the draining lymph nodes of both EAE-susceptible Dark Agouti (DA) and EAE-resistant Albino Oxford (AO) rats. However, the increase in ER stress markers was more pronounced in AO rats. CFA alone also induced ER stress, but the effect was weaker and less sustained compared to full immunization. The ultrastructural analysis of DA lymph node tissue by electron microscopy revealed ER dilatation in lymphocytes, macrophages, and plasma cells, while immunoblot analysis of CD3-sorted lymph node cells demonstrated the increase in ER stress/UPR markers in both CD3+ (T cell) and CD3− (non-T) cell compartments. A positive correlation was observed between the levels of ER stress/UPR markers in the CNS-infiltrated mononuclear cells and the clinical activity of the disease. Finally, the reduction of EAE clinical signs by ER stress inhibitor ursodeoxycholic acid was associated with the decrease in the expression of mRNA encoding pro-inflammatory cytokines TNF and IL-1β, and encephalitogenic T cell cytokines IFN-γ and IL-17. Collectively, our data indicate that ER stress response in immune cells might be an important pathogenetic factor and a valid therapeutic target in the inflammatory damage of the CNS.

Reducing low-value interhospital transfers for mild traumatic brain injury.

The modified Brain Injury Guidelines (mBIG) were developed to stratify traumatic brain injuries (TBIs) and improve health care utilization by selectively requiring repeat imaging, intensive care unit admission, and neurosurgical (NSG) consultation. The goal of this study is to assess safety and potential resource savings associated with the application of mBIG on interhospital patient transfers for TBI. Adult patients with TBI transferred to our Level I trauma center from January 2017 to December 2022 meeting mBIG inclusion criteria were retrospectively stratified into mBIG1, mBIG2, and mBIG3 based on initial clinicoradiological factors. At the time, our institution routinely admitted patients with TBI and intracranial hemorrhage (ICH) to the intensive care unit and obtained a repeat head computed tomography with NSG consultation, independent of TBI severity or changes in neurological examination. The primary outcome was progression of ICH on repeat imaging and/or NSG intervention. Secondary outcomes included length of stay and financial charges. Subgroup analysis on isolated TBI without significant extracranial injury was performed. Over the 6-year study period, 289 patients were classified into mBIG1 (61; 21.1%), mBIG2 (69; 23.9%), and mBIG3 (159; 55.0%). Of mBIG1 patients, 2 (2.9%) had radiological progression to mBIG2 without clinical decline, and none required NSG intervention. Of mBIG2, 2 patients (3.3%) progressed to mBIG3, and both required NSG intervention. More than 35% of transferred patients had minor isolated TBI. For mBIG1 and mBIG2, the median hospitalization charges per patient were $152,296 and $149,550, respectively, and the median length of stay was 4 and 5 days, respectively, with the majority downgraded from the intensive care unit within 48 hours. Clinically significant progression of ICH occurred infrequently in 1.5% of patients with mBIG1 and mBIG2 injuries. More than 35% of interfacility transfers for minor isolated TBI meeting mBIG1 and 2 criteria are low value and may potentially be safely deferred in an urban health care setting. Therapeutic/Care Management; Level IV.

RNA splicing regulator EIF3D regulates the tumor microenvironment through immunogene-related alternative splicing in head and neck squamous cell carcinoma.

Study finds that eukaryotic translation initiation factor 3 subunit D (EIF3D) may play an important role in aberrant alternative splicing (AS) events in tumors. AS possesses a pivotal role in both tumour progression and the constitution of the tumour microenvironment (TME). Regrettably, our current understanding of AS remains circumscribed especially in the context of immunogene-related alternative splicing (IGAS) profiles within Head and Neck Squamous Cell Carcinoma (HNSC). In this study, we comprehensively analyzed the function and mechanism of action of EIF3D by bioinformatics analysis combined with in vitro cellular experiments, and found that high expression of EIF3D in HNSC was associated with poor prognosis of overall survival (OS) and progression-free survival (PFS). The EIF3D low expression group had a higher degree of immune infiltration and better efficacy against PD1 and CTLA4 immunotherapy compared to the EIF3D high expression group. TCGA SpliceSeq analysis illustrated that EIF3D influenced differentially spliced alternative splicing (DSAS) events involving 105 differentially expressed immunogenes (DEIGs). We observed an induction of apoptosis and a suppression of cell proliferation, migration, and invasion in EIF3D knock-down FaDu cells. RNA-seq analysis unveiled that 531 genes exhibited differential expression following EIF3D knockdown in FaDu cells. These include 52 DEIGs. Furthermore, EIF3D knockdown influenced the patterns of 1923 alternative splicing events (ASEs), encompassing 129 IGASs. This study identified an RNA splicing regulator and revealed its regulatory role in IGAS and the TME of HNSC, suggesting that EIF3D may be a potential target for predicting HNSC prognosis and immunotherapeutic response.

Effect of moxibustion combined with intraperitoneal injection of benazepril on endoplasmic reticulum stress-related protein phosphorylation in rats with chronic heart failure.

To observe the effect of moxibustion at "Xinshu"(BL15) and "Feishu"(BL13) combined with intraperitoneal injection of benazepril on cardiac function and phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (elF2α) proteins in myocardium of rats with chronic heart failure (CHF), so as to explore its potential mechanism underlying improvement of CHF. A total of 42 male SD rats were randomly assigned to blank control (n=10), CHF model (n=7), medication (benazepril, n=8), moxibustion (n=8) and moxibustion+benazepril (n=9) groups, after cardiac ultrasound model identification and elimination of the dead. The CHF model was established by intraperitoneal injection of doxorubicin hydrochloride (DOX), once every week for 6 weeks. Mild moxibustion was applied to bilateral BL15 and BL13 regions for 20 min, once daily for 3 weeks. The rats of the medication group and moxibustion+benazepril group (benazepril was given first, followed by moxibustion) received intraperitoneal injection of benazepril (0.86 mg/kg) solution once daily for 3 weeks . The cardiac ejection fraction (EF) and left ventricular fractional shortening (FS) were measured using echocardiography. Histopathological changes of the cardiac muscle tissue were observed under light microscope after hematoxylin-eosin (H.E.) staining. Serum contents of B-type brain natriuretic peptide (BNP) and angiotensin Ⅱ (AngⅡ) were measured by enzyme-linked immunosorbent assay (ELISA). The expressions of phospho-PERK (p-PERK) and phospho-elF2α (p-elF2α) in the myocardium were detected by Western blot. Compared with the blank control group, the EF and FS of the left cardiac ventricle were significantly decreased (P<0.01), while the contents of serum BNP and AngⅡ, and expression levels of p-PERK and p-eIF2α significantly increased in the model group (P<0.01). In comparison with the model group, both the decreased EF and FS and the increased BNP and AngⅡ contents as well as p-PERK and p-elF2α expression levels were reversed by moxibustion, medication and moxibustion+benazepril (P<0.01). The effects of moxibustion+benazepril were markedly superior to those of simple moxibustion and simple medication in raising the levels of EF and FS rate and in down-regulating the contents of BNP, Ang Ⅱ, levels of p-PERK and p-elF2α (P<0.01, P<0.05). Outcomes of H.E. staining showed irregular arrangement of cardiomyocytes, cell swelling, vacuole and inflammatory infiltration in the model group, which was relatively milder in the 3 treatment groups. The effects of moxibustion+benazepril were superior to those of moxibustion or benazepril. Moxibustion combined with Benazepril can improve the cardiac function in CHF rats, which may be related to its functions in down-regulating the expression levels of myocardial p-PERK and p-elF2α to inhibit endoplasmic reticulum stress response.

Burden from Study Questionnaire on Patient Fatigue in Qualitative Congestive Heart Failure Research.

Mixed methods research forms the backbone of translational research methodologies. Qualitative research and subjective data lead to hypothesis generation and ideas that are then proven via quantitative methodologies and gathering objective data. In this vein, clinical trials that generate subjective data may have limitations, when they are not followed through with quantitative data, in terms of their ability to be considered gold standard evidence and inform guidelines and clinical management. However, since many research methods utilise qualitative tools, an initial factor is that such tools can create a burden on patients and researchers. In addition, the quantity of data and its storage contributes to noise and quality issues for its primary and post hoc use. This paper discusses the issue of the burden of subjective data collected and fatigue in the context of congestive heart failure (CHF) research. The CHF population has a high baseline morbidity, so no doubt the focus should be on the content; however, the lengths of the instruments are a product of their vigorous validation processes. Nonetheless, as an important source of hypothesis generation, if a choice of follow-up qualitative assessment is required for a clinical trial, shorter versions of the questionnaire should be used, without compromising the data collection requirements; otherwise, we need to invest in this area and find suitable solutions.

Solving Spectrum Unmixing as a Multi-Task Bayesian Inverse Problem with Latent Factors for Endmember Variability

With the increasing customization of spectrometers, spectral unmixing has become a widely used technique in fields such as remote sensing, textiles, and environmental protection. However, endmember variability is a common issue for unmixing, where changes in lighting, atmospheric, temporal conditions, or the intrinsic spectral characteristics of materials, can all result in variations in the measured spectrum. Recent studies have employed deep neural networks to tackle endmember variability. However, these approaches rely on generic networks to implicitly resolve the issue, which struggles with the ill-posed nature and lack of effective convergence constraints for endmember variability. This paper proposes a streamlined multi-task learning model to rectify this problem, incorporating abundance regression and multi-label classification with Unmixing as a Bayesian Inverse Problem, denoted as BIPU. To address the issue of the ill-posed nature, the uncertainty of unmixing is quantified and minimized through the Laplace approximation in a Bayesian inverse solver. In addition, to improve convergence under the influence of endmember variability, the paper introduces two types of constraints. The first separates background factors of variants from the initial factors for each endmember, while the second identifies and eliminates the influence of non-existent endmembers via multi-label classification during convergence. The effectiveness of this model is demonstrated not only on a self-collected near-infrared spectral textile dataset (FENIR), but also on three commonly used remote sensing hyperspectral image datasets, where it achieves state-of-the-art unmixing performance and exhibits strong generalization capabilities.

Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer.

Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.