Diffusivities and Atomic Mobilities in BCC Ti-Fe-Cr Alloys.

In this research, the diffusion behaviors within the Ti-Fe-Cr ternary system were examined at the temperatures of 1273 K and 1373 K through the diffusion couple technique. This study led to the determination of both ternary inter-diffusion and impurity diffusion coefficients in the body-centered cubic (bcc) phase for the Ti-Fe-Cr alloy, utilizing the Whittle-Green and Hall methods. The statistics show that the average diffusion coefficients D˜FeFeTi and D˜CrCrTi measured at 1273 K were 1.34 × 10-12 and 3.66 × 10-13, respectively. At 1373 K, the average values of D˜FeFeTi and D˜CrCrTi were 4.89 × 10-12 and 1.43 × 10-12. By adopting the CALPHAD method, a self-consistent database for atomic mobility in the bcc phase of the Ti-Fe-Cr system was established. This database underwent refinement by comparing the newly acquired diffusion coefficients with data from the existing literature. Diffusion simulations for the diffusion couples were performed, drawing on the established database. The error between the simulated diffusion coefficient and the experimental measurement data is within 15%, and the simulated data of the component distance distribution and diffusion path are in good agreement with the experimental data. The simulations generated results that aligned well with the observed experimental diffusion characteristics, thereby affirming the reliability and accuracy of the database.

Role of the score for the targeting of atrial fibrillation (STAF) combined with D-dimer in screening ischemic stroke patients with atrial fibrillation.

Background: We aim to explore the effect of the score for the targeting of atrial fibrillation (STAF) combined with the serum D-dimer (DD) level in screening acute ischemic stroke patients with atrial fibrillation (AF). Methods: This study is a retrospective case observation study. This study consecutively selected patients with acute ischemic stroke who were hospitalized in the Department of Neurology at Zhuhai Hospital Affiliated with Jinan University from February 2019 to February 2021. Venous blood was drawn from all patients within 24 hours of hospitalization for DD detection. In accordance with the medical records, the patients were classified into an AF group and a non-AF group and were scored according to the STAF standard. A combined test method was used to estimate the diagnostic screening value of the STAF combined with the DD value for acute ischemic stroke patients with AF.

Evaluation of the Prognostic Role of Neutrophil-Lymphocyte Ratio, C-Reactive Protein-Albumin Ratio, and Platelet-Lymphocyte Ratio in Patients with the Co-Presentation of Coronary Artery Disease and COVID-19.

Aim: The purpose of this study was to investigate the role of neutrophil-lymphocyte ratio (NLR), C-reactive protein-albumin ratio (CAR), and platelet-lymphocyte ratio (PLR) in the prognosis of patients with coronary artery disease (CAD) complicated with coronavirus disease 2019 (COVID-19). Methods: This study included 265 patients. A receiver operating characteristic (ROC) curve analysis was performed to preliminarily evaluate the predictive ability of NLR, CAR, and PLR for all-cause death. The primary outcome was all-cause death during hospitalization, while the secondary outcomes were cardiovascular death and respiratory failure death. The Cox proportional hazard model with adjusted covariates was used to analyze the cumulative risk of outcomes. We also conducted subgroup analyses based on the acute and chronic characteristics of CAD. Propensity score matching (PSM) was used to further evaluate the robustness of the primary outcome. Results: The ROC curve analysis results showed that the area under curve (AUC) values were 0.686 (95% CI 0.592-0.781, P<0.001) for NLR, 0.749 (95% CI 0.667-0.832, P<0.001) for CAR, and 0.571 (95% CI 0.455-0.687, P=0.232) for PLR. The Cox proportional hazard model showed that trends in NLR and PLR did not affect the risk of all-cause death (P=0.096 and P=0.544 for trend, respectively), but a higher CAR level corresponded to a higher risk of all-cause death (P<0.001 for trend). Similarly, The trends of NLR and PLR did not affect the risk of cardiovascular death and respiratory failure death, while a higher CAR level corresponded to a higher risk of cardiovascular death and respiratory failure death. The results of subgroup analyses and PSM were consistent with the total cohort. Conclusion: In patients with CAD complicated with COVID-19, a higher CAR level corresponded to a higher risk of all-cause death, cardiovascular death, and respiratory failure death, while trends in NLR and PLR did not.

Inflammatory risk of albumin combined with C-reactive protein predicts long-term cardiovascular risk in patients with diabetes.

AIMS: The purpose of this study was to evaluate the predictive value of inflammatory risk as defined by the Glasgow Prognostic Score (GPS) for cardiovascular death in patients with diabetes. METHODS: This study included 4956 patients (≥18 years old) with diabetes in the National Health and Nutrition Survey from 1999 to 2010. The mortality rate was determined by the correlation with the national death index on December 31, 2019. The GPS was composed of the serum C-reactive protein and the albumin. The primary outcome was cardiovascular death and the secondary outcome was all-cause death. The Cox proportional risk model adjusted for demographic factors and traditional cardiovascular risk factors was used to analyze the cumulative risk of outcomes. RESULTS: Among 4956 diabetes patients with a median follow-up of 10.9 years, 601 cardiovascular deaths and 2187 all-cause deaths were recorded. After adequate model adjustment, compared with the low GPS group, the high GPS group (HR, 1.257 (1.007-1.570), P = 0.043) had a higher cardiovascular mortality. Compared with the low GPS group, the all-cause mortality of the high GPS group (HR, 1.394 (1.245-1.560), P < 0.001) was higher. The results of subgroup analyses were similar with that of the overall cohort. CONCLUSIONS: The inflammatory risk as defined by the GPS was closely related to the increased risk of cardiovascular and all-cause death in patients with diabetes. It may be a convenient and efficient clinical practical risk assessment tool for patients with diabetes.

Mitophagy activation by rapamycin enhances mitochondrial function and cognition in 5×FAD mice.

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by severe mitochondrial dysfunction, which is an intracellular process that is significantly compromised in the early stages of AD. Mitophagy, the selective removal of damaged mitochondria, is a potential therapeutic strategy for AD. Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, augmented autophagy and mitigated cognitive impairment. Our study revealed that rapamycin enhances cognitive function by activating mitophagy, alleviating neuronal loss, and improving mitochondrial dysfunction in 5 ×FAD mice. Interestingly, the neuroprotective effect of rapamycin in AD were negated by treatment with 3-MA, a mitophagy inhibitor. Overall, our findings suggest that rapamycin ameliorates cognitive impairment in 5 ×FAD mice via mitophagy activation and its downstream PINK1-Parkin pathway, which aids in the clearance of amyloid-ß (Aß) and damaged mitochondria. This study reveals a novel mechanism involving mitophagy regulation underlying the therapeutic effect of rapamycin in AD. This study provides new insights and therapeutic targets for rapamycin in the treatment of AD. However, there are still some shortcomings in this topic; if we can further knock out the PINK1/Parkin gene in animals or use siRNA technology, we can further confirm the experimental results.

Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390.

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

STING Agonist-Loaded Nanoparticles Promotes Positive Regulation of Type I Interferon-Dependent Radioimmunotherapy in Rectal Cancer.

Hypoxia-associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X-ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon-dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and αPD-1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC.

Activation of mitophagy improves cognitive dysfunction in diabetic mice with recurrent non-severe hypoglycemia.

Recurrent non-severe hypoglycemia (RH) in patients with diabetes might be associated with cognitive impairment. Previously, we found that mitochondrial dysfunction plays an important role in this pathological process; however, the mechanism remains unclear. The objective of this study was to determine the molecular mechanisms of mitochondrial damage associated with RH in diabetes mellitus (DM). We found that RH is associated with reduced hippocampal mitophagy in diabetic mice, mainly manifested by reduced autophagosome formation and impaired recognition of impaired mitochondria, mediated by the PINK1/Parkin pathway. The same impaired mitophagy initiation was observed in an in vitro high-glucose cultured astrocyte model with recurrent low-glucose interventions. Promoting autophagosome formation and activating PINK1/Parkin-mediated mitophagy protected mitochondrial function and cognitive function in mice. The results showed that impaired mitophagy is involved in the occurrence of mitochondrial dysfunction, mediating the neurological impairment associated with recurrent low glucose under high glucose conditions.

Potential risk factors for mild cognitive impairment among patients with type 2 diabetes experiencing hypoglycemia.

AIMS: This study examined the association between hypoglycemia and mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM) and identified risk factors for MCI in patients with hypoglycemia. METHODS: In this retrospective study, 328 patients with T2DM were screened in 2019 and followed up in 2022. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). The diagnosis of MCI was based on established criteria. Risk ratio (RR) with 95 % confidence intervals (CI) was calculated to estimate the risk of MCI. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for MCI in those with hypoglycemia. RESULTS: Patients with hypoglycemia had lower cognitive performance 3 years later. The RR of MCI was 2.221 (95 % CI 1.269-3.885). Multivariate logistic analysis showed that low grip strength, existing diabetic retinopathy (DR), and multiple hypoglycemia episodes were associated with higher odds of MCI in patients with hypoglycemia (adjusted odds ratio [OR] 0.909 [95 % CI 0.859-0.963]), 3.078 [95 % CI 1.158-12.358], and 4.642 [95 % CI 1.284-16.776], respectively, all P < 0.05). CONCLUSIONS: Hypoglycemia increased MCI risk among patients with T2DM. Low grip strength, DR, and multiple hypoglycemia episodes may be potential risk factors for hypoglycemia-associated MCI.

Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation.

BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. METHODS: Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. RESULTS: We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8+ T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. CONCLUSIONS: Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice.

GLP-1 Receptor Agonist Improves Mitochondrial Energy Status and Attenuates Nephrotoxicity In Vivo and In Vitro.

High-sugar and high-fat diets cause significant harm to health, especially via metabolic diseases. In this study, the protective effects of the antidiabetic drug exenatide (synthetic exendin-4), a glucagon-like peptide 1 (GLP-1) receptor agonist, on high-fat and high-glucose (HFHG)-induced renal injuries were investigated in vivo and in vitro. In vivo and in vitro renal injury models were established. Metabolomic analysis based on 1H-nuclear magnetic resonance was performed to examine whether exenatide treatment exerts a protective effect against kidney injury in diabetic rats and to explore its potential molecular mechanism. In vivo, 8 weeks of exenatide treatment resulted in the regulation of most metabolites in the diabetes mellitus group. In vitro results showed that exendin-4 restored the mitochondrial functions of mesangial cells, which were perturbed by HFHG. The effects of exendin-4 included the improved antioxidant capacity of mesangial cells, increased the Bcl-2/Bax ratio, and reduced protein expression of cyt-c and caspase-3 activation. In addition, exendin-4 restored mesangial cell energy metabolism by increasing succinate dehydrogenase and phosphofructokinase activities and glucose consumption while inhibiting pyruvate dehydrogenase E1 activity. In conclusion, GLP-1 agonists improve renal injury in diabetic rats by ameliorating metabolic disorders. This mechanism could be partially related to mitochondrial functions and energy metabolism.

Disturbed hippocampal histidine metabolism contributes to cognitive impairment induced by recurrent nonsevere hypoglycemia in diabetes.

Hypoglycemia is a common adverse reaction to glucose-lowering treatment. Diabetes mellitus (DM) combined with recurrent nonsevere hypoglycemia (RH) can accelerate cognitive decline. Currently, the metabolic pattern changes in cognition-related brain regions caused by this combined effect of DM and RH (DR) remain unclear. In this study, we first characterized the metabolic profiles of the hippocampus in mice exposed to DR using non-targeted metabolomic platforms. Our results showed that DR induced a unique metabolic pattern in the hippocampus, and several significant differences in metabolite levels belonging to the histidine metabolism pathway were discovered. Based on these findings, in the follow-up experiment, we found that histidine treatment could attenuate the cognitive impairment and rescue the neuronal and synaptic damage induced by DR in the hippocampus, which are closely related to ameliorated mitochondrial injury. These findings provide new insights into the metabolic mechanisms of the hippocampus in the progression of DR, and l-histidine supplementation may be a potential metabolic therapy in the future.

P-doped Co3S4/NiS2 heterostructures embedded in N-doped carbon nanoboxes: Synergistical electronic structure regulation for overall water splitting.

Water splitting using transition metal sulfides as electrocatalysts has gained considerable attention in the field of renewable energy. However, their electrocatalytic activity is often hindered by unfavorable free energies of adsorbed hydrogen and oxygen-containing intermediates. Herein, phosphorus (P)-doped Co3S4/NiS2 heterostructures embedded in N-doped carbon nanoboxes were rationally synthesized via a pyrolysis-sulfidation-phosphorization strategy. The hollow structure of the carbon matrix and the nanoparticles contained within it not only result in a high specific surface area, but also protects them from corrosion and acts as a conductive pathway for efficient electron transfer. Density functional theory (DFT) calculations indicate that the introduction of P dopants improves the conductivity of NiS2 and Co3S4, promotes the charge transfer process, and creates new electrocatalytic sites. Additionally, the NiS2-Co3S4 heterojunctions can enhance the adsorption efficiency of hydrogen intermediates (H*) and lower the energy barrier of water splitting via a synergistic effect with P-doping. These characteristics collectively enable the titled catalyst to exhibit excellent electrocatalytic activity for water splitting in alkaline medium, requiring only small overpotentials of 150 and 257 mV to achieve a current density of 10 mA cm-2 for hydrogen and oxygen evolution reactions, respectively. This work sheds light on the design and optimization of efficient electrocatalysts for water splitting, with potential implications for renewable energy production.

Neural Novel Actor: Learning a Generalized Animatable Neural Representation for Human Actors.

We propose a new method for learning a generalized animatable neural human representation from a sparse set of multi-view imagery of multiple persons. The learned representation can be used to synthesize novel view images of an arbitrary person and further animate them with the user's pose control. While most existing methods can either generalize to new persons or synthesize animations with user control, none of them can achieve both at the same time. We attribute this accomplishment to the employment of a 3D proxy for a shared multi-person human model, and further the warping of the spaces of different poses to a shared canonical pose space, in which we learn a neural field and predict the person- and pose-dependent deformations, as well as appearance with the features extracted from input images. To cope with the complexity of the large variations in body shapes, poses, and clothing deformations, we design our neural human model with disentangled geometry and appearance. Furthermore, we utilize the image features both at the spatial point and on the surface points of the 3D proxy for predicting person- and pose-dependent properties. Experiments show that our method significantly outperforms the state-of-the-arts on both tasks.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Amorphous and defective Co-P-O@NC ball-in-ball hollow structure for highly efficient electrocatalytic overall water splitting.

Electrochemical water splitting using hollow and defect-rich catalysts has emerged as a promising strategy for efficient hydrogen production. However, the rational design and controllable synthesis of such catalysts with intricate morphology and composition present significant challenges. Herein, we propose a template-engaged approach to fabricate a novel ball-in-ball hollow structure of Co-P-O@N-doped carbon with abundant oxygen vacancies. The synthesis process involves the preparation of uniform cobalt-glycerate (Co-gly) polymer microspheres as precursors, followed by surface coating with ZIF-67 layer, adjustable chemical etching by phytic acid, and controllable pyrolysis at high temperature. The resulting ball-in-ball structure offers a large number of accessible active sites and high redox reaction centers, facilitating efficient charge transport, mass transfer, and gas evolution, which are beneficial for the acceleration of electrocatalytic reaction. Additionally, density functional theory (DFT) calculations indicate that the incorporation of oxygen and the presence of Co-P dangling bonds in CoP significantly enhance the adsorption of oxygenated species, leading to improved intrinsic electroactivity at the single-site level. As a sequence, the titled catalyst exhibits remarkable electrocatalytic activity and stability for water splitting in alkaline media. Notably, it only requires a low overpotential of 283 mV to achieve a current density of 10 mA cm-2 for the oxygen evolution reaction. This work may provide some new insights into the design of complex hollow structures of phosphides with abundant defects for energy conversion.

Co-generation of hydroxyl and sulfate radicals via homogeneous and heterogeneous bi-catalysis with the EO-PS-EF tri-coupling system for efficient removal of refractory organic pollutants.

Advanced oxidation processes are commonly considered one of the most effective techniques to degrade refractory organic pollutants, but the limitation of a single process usually makes it insufficient to achieve the desired treatment. This work introduces, for the first time, a highly-efficient coupled advanced oxidation process, namely Electro-Oxidation-Persulfate-Electro-Fenton (EO-PS-EF). Leveraging the EO-PS-EF tri-coupling system, diverse contaminants can be highly efficiently removed with the help of reactive hydroxyl and sulfate radicals generated via homogeneous and heterogeneous bi-catalysis, as certified by radical quenching and electron spin resonance. Concerning degradation of tetracycline (TC), the EO-PS-EF system witnessed a fast pseudo-first-order reaction kinetic constant of 2.54 × 10-3 s-1, ten times that of a single EO system and three-to-four times that of a binary system (EO-PS or EO-EF). In addition, critical parameters (e.g., electrolyte, pH and temperature) are systematically investigated. Surprisingly, after 100 repetitive trials TC removal can still reach 100% within 30 min and no apparent morphological changes to electrode materials were observed, demonstrating its long-term stability. Finally, its universality was demonstrated with effective degradation of diverse refractory contaminants (i.e., antibiotics, dyes and pesticides).

Smoking is a Factor in Discordance Between QuantiFERONTB Gold Assay and Tuberculosis Etiology: Especially in Older Patients.

Purpose: Exploring whether smoking is an influencing factor for the inconsistency between QuantiFERONTB Gold assay (QFT-GIT) and tuberculosis etiology. Patients and Methods: The clinical data of patients who were confirmed positive for Mycobacterium tuberculosis (MTB) after undergoing QFT-GIT testing from September 2017 to August 2021 were retrospectively analyzed. Chi-square and rank-sum tests were used to compare the differences in characteristics between smokers and non-smokers. Logistic regression was used to adjust for confounding factors affecting smoking. Propensity score matching (PSM) was used to verify the above conclusions again. Results: Positive results of tuberculosis etiology were adopted as the standard, the incidence of inconsistent results between QFT-GIT and tuberculosis etiology was 8.90% (108/1213), of which the false negative rate was 6.27% (76/1213) and the indeterminate rate was 2.64% (32/1213). In the overall population, the smokers had a lower level of basal IFN-γ (Z=-2.079, P=0.038). Among 382 elderly (≥65 years old) patients, the smokers had lower levels of antigen-stimulated IFN-γ (Z=-2.838, P=0.005). After performing BOX-COX transformation on all non-normally distributed data, logistic stepwise regression was used to adjust confounding factors. The results showed that smoking was an influencing factor for the inconsistency between QFT-GIT and tuberculosis etiology results (OR=1.69, P=0.020). Using PSM for 1:2 matching, the results showed that smoking was still an independent risk factor for the inconsistent results of QFT-GIT and tuberculosis etiology (OR= 1.95, P=0.019). Age-stratified analysis showed that smoking was an independent risk factor in discordance between QFT-GIT and tuberculosis etiology in patients aged ≥65 years (OR=2.40, P=0.005), but not in patients aged <65 years (P > 0.05). Conclusion: Smoking can reduce the body's IFN-γ release ability, and smoking (especially the elderly) is an influencing factor for the inconsistency between QFT-GIT and tuberculosis etiological results.

Mitophagy disorder mediates cardiac deterioration induced by severe hypoglycemia in diabetic mice.

Severe hypoglycemia is closely related to adverse cardiovascular outcomes in patients with diabetes; however, the specific mechanism remains unclear. We previously found that severe hypoglycemia aggravated myocardial injury and cardiac dysfunction in diabetic mice, and that the mechanism of damage was related to mitochondrial oxidative stress and dysfunction. Based on the key regulatory role of mitophagy in mitochondrial quality control, this study aimed to further explore whether the myocardial damage caused by severe hypoglycemia is related to insufficient mitophagy and to clarify their underlying regulatory relationship. After severe hypoglycemia, mitochondrial reactive oxygen species increased, mitochondrial membrane potential and ATP content decreased, and pathological mitochondrial damage was aggravated in the myocardium of diabetic mice. This was accompanied by decreased mitochondrial biosynthesis, increased fusion, and downregulated PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy. Treating diabetic mice with the mitophagy activator and polyphenol metabolite urolithin A activated PINK1/Parkin-dependent mitophagy, reduced myocardial oxidative stress and mitochondrial damage associated with severe hypoglycemia, improved mitochondrial function, alleviated myocardial damage, and ultimately improved cardiac function. Thus, we provide insight into the prevention and treatment of diabetic myocardial injury caused by hypoglycemia to reduce adverse cardiovascular outcomes in patients with diabetes.

A novel anoikis-related gene prognostic signature and its correlation with the immune microenvironment in colorectal cancer.

Background: Anoikis is a type of apoptosis associated with cell detachment. Resistance to anoikis is a focal point of tumor metastasis. This study aimed to explore the relationship among anoikis-related genes (ARGs), immune infiltration, and prognosis in colorectal cancer (CRC). Methods: The transcriptome profile and clinical data on patients with CRC were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Patients were divided into two clusters based on the expression of ARGs. Differences between the two ARG molecular subtypes were analyzed in terms of prognosis, functional enrichment, gene mutation frequency, and immune cell infiltration. An ARG-related prognostic signature for predicting overall survival in patients with CRC was developed and validated using absolute value convergence and selection operator (LASSO) regression analysis. The correlation between the signature risk score and clinicopathological features, immune cell infiltration, immune typing, and immunotherapy response was analyzed. The risk score combined with clinicopathological characteristics was used to construct a nomogram to assess CRC patients' prognosis. Results: Overall, 151 ARGs were differentially expressed in CRC. Two ARG subtypes, namely, ARG-high and ARG-low groups, were identified and correlated with CRC prognosis. The gene mutation frequency and immune, stromal, and ESTIMATE scores of the ARG-high group were higher than those of the ARG-low group. Moreover, CD8, natural killer cells, M1 macrophages, human leukocyte antigen (HLA), and immune checkpoint-related genes were significantly increased in the ARG-high group. An optimized 25-gene CRC prognostic signature was successfully constructed, and its prognostic predictive ability was validated. The high-risk score was correlated with T, N, M, and TNM stages. Risk scores were negatively correlated with dendritic cells, eosinophils, and CD4 cells, and significantly positively correlated with regulatory T cells. Patients in the high-risk group were more likely to exhibit immune unresponsiveness. Finally, the nomogram model was constructed and showed good prognostic predictive power. Conclusion: ARGs are associated with clinicopathological features and the prognosis of CRC, and play important roles in the immune microenvironment. Herein, we underpinned the usefulness of ARGs in CRC to develop more effective immunotherapy techniques.