Learning spatial structures of proteins improves protein-protein interaction prediction.

Spatial structures of proteins are closely related to protein functions. Integrating protein structures improves the performance of protein-protein interaction (PPI) prediction. However, the limited quantity of known protein structures restricts the application of structure-based prediction methods. Utilizing the predicted protein structure information is a promising method to improve the performance of sequence-based prediction methods. We propose a novel end-to-end framework, TAGPPI, to predict PPIs using protein sequence alone. TAGPPI extracts multi-dimensional features by employing 1D convolution operation on protein sequences and graph learning method on contact maps constructed from AlphaFold. A contact map contains abundant spatial structure information, which is difficult to obtain from 1D sequence data directly. We further demonstrate that the spatial information learned from contact maps improves the ability of TAGPPI in PPI prediction tasks. We compare the performance of TAGPPI with those of nine state-of-the-art sequence-based methods, and TAGPPI outperforms such methods in all metrics. To the best of our knowledge, this is the first method to use the predicted protein topology structure graph for sequence-based PPI prediction. More importantly, our proposed architecture could be extended to other prediction tasks related to proteins.

Identification of key genes of diabetic cardiomyopathy in hiPSCs-CMs based on bioinformatics analysis.

Diabetic cardiomyopathy (DbCM) is one of the most common vascular complications of diabetes, and can cause heart failure and threaten the life of patients. The pathogenesis is complex, and key genes have not fully identified. In this study, bioinformatics analysis was used to predict DbCM-related gene targets. Published datasets from the NCBI Gene Expression Omnibus with accession numbers GSE62203 and GSE197850 were selected for analysis. Differentially expressed genes (DEGs) were identified by the online tool GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID online database. Protein-protein interaction network construction and hub gene identification were performed using STRING and Cytoscape. We used 30 mM and 1 µM hydrocortisone-stimulated AC16 cells as an in vitro model of diabetic cardiomyopathy. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression levels of hub genes. A total of 73 common DEGs were identified in both datasets, including 47 upregulated and 26 downregulated genes. GO and KEGG pathway enrichment analyses revealed that the DEGs were significantly enriched in metabolism, hypoxia response, apoptosis, cell proliferation regulation, and cytoplasmic and HIF signalling pathways. The top 10 hub genes were LDHA, PGK1, SLC2A1, ENO1, PFKFB3, EGLN1, MYC, PDK1, EGLN3 and BNIP3. In our in vitro study, we found that PGK1, SLC2A1, PFKFB3, EGLN1, MYC, EGLN3 and BNIP3 were upregulated, ENO1 was downregulated, and LDHA was unchanged. Except for PGK1 and ENO1, these hub genes have been previously reported to be involved in DbCM. In summary, we identified DEGs and hub genes and first reported PGK1 and ENO1 in DbCM, which may serve as potential candidate genes for DbCM targeted therapy.

Host-guest interaction induced room-temperature phosphorescence enhancement of organic dyes: a computational study.

To achieve the effective regulation of organic room temperature phosphorescence (RTP) in supramolecular systems, the elucidation of host-guest interactions in RTP is of vital importance. Herein, we employed two organic dyes (PYCl and PYBr) and their four host-guest complexes with CB[6] and CB[7] and explored the mechanism of host-guest interaction induced RTP enhancement using quantum mechanics/molecular mechanics (QM/MM) approach. For the two organic dyes, we found that the better RTP performance of PYBr than PYCl is attributed to intersystem crossing (ISC) augmentation induced by the heavy atom effect. Binding to CB[6] through host-guest interactions can simultaneously accelerate the radiative decay process by increasing the transition dipole moment of T1 → S0 (µT1→S0), block the nonradiative decay process, and promote the ISC process, eventually leading to a remarkably boosted RTP. Upon complexation, the conversion of S1 from 1(n, π*) to 1(π, π*) is key to µT1→S0 enhancement; reduced reorganization energies reflect the suppression of the nonradiative decay process by restricting the rotation of rings A and B in organic dyes. In addition, the promoted ISC process is due to the activation of more ISC channels between S1 and high-lying triplet states with large spin-orbital coupling constants and small energy gap. The case of CB[7]-type complexes is much different, because of the extremely large cavity size of CB[7] for encapsulation. This work proposes the mechanism of host-guest interaction-induced RTP enhancement of organic dyes, thus laying a solid foundation for the rational design of advanced RTP materials based on supramolecular assemblies.

Efficient FMT reconstruction based on L1-αL2 regularization via half-quadratic splitting and a two-probe separation light source strategy.

Fluorescence molecular tomography (FMT) can achieve noninvasive, high-contrast, high-sensitivity three-dimensional imaging in vivo by relying on a variety of fluorescent molecular probes, and has excellent clinical transformation prospects in the detection of tumors in vivo. However, the limited surface fluorescence makes the FMT reconstruction have some ill-posedness, and it is difficult to obtain the ideal reconstruction effect. In this paper, two different emission fluorescent probes and L 1-L 2 regularization are combined to improve the temporal and spatial resolution of FMT visual reconstruction by introducing the weighting factor α and a half-quadratic splitting alternating optimization (HQSAO) iterative algorithm. By introducing an auxiliary variable, the HQSAO method breaks the sparse FMT reconstruction task into two subproblems that can be solved in turn: simple reconstruction and image denoising. The weight factor α (α>1) can increase the weight of nonconvex terms to further promote the sparsity of the algorithm. Importantly, this paper combines two different dominant fluorescent probes to achieve high-quality reconstruction of dual light sources. The performance of the proposed reconstruction strategy was evaluated by digital mouse and nude mouse single/dual light source models. The simulation results show that the HQSAO iterative algorithm can achieve more excellent positioning accuracy and morphology distribution in a shorter time. In vivo experiments also further prove that the HQSAO algorithm has advantages in light source information preservation and artifact suppression. In particular, the introduction of two main emission fluorescent probes makes it easy to separate and reconstruct the dual light sources. When it comes to localization and three-dimensional morphology, the results of the reconstruction are much better than those using a fluorescent probe, which further facilitates the clinical transformation of FMT.

Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice.

Diabetic kidney disease is one of the most serious complications of diabetes. Although diabetic kidney disease can be effectively controlled through strict blood glucose management and corresponding symptomatic treatment, these therapies cannot reduce its incidence in diabetic patients. The sodium-glucose cotransporter 2 (SGLT2) inhibitors and the traditional Chinese herb "Gegen" have been widely used in diabetes-related therapy. However, it remains unclear whether the combined use of these two kinds of medicines contributes to an increased curative effect on diabetic kidney disease. In this study, we examined this issue by evaluating the efficacy of the combination of puerarin, an active ingredient of Gegen, and canagliflozin, an SGLT2 inhibitor for a 12-week intervention using a mouse model of diabetes. The results indicated that the combination of puerarin and canagliflozin was superior to canagliflozin alone in improving the metabolic and renal function parameters of diabetic mice. Our findings suggested that the renoprotective effect of combined puerarin and canagliflozin in diabetic mice was achieved by reducing renal lipid accumulation. This study provides a new strategy for the clinical prevention and treatment of diabetic kidney disease. The puerarin and SGLT2 inhibitor combination therapy at the initial stage of diabetes may effectively delay the occurrence of diabetic kidney injury, and significantly alleviate the burden of renal lipotoxicity.

Riboflavin integrates cellular energetics and cell cycle to regulate maize seed development.

Riboflavin is the precursor of essential cofactors for diverse metabolic processes. Unlike animals, plants can de novo produce riboflavin through an ancestrally conserved pathway, like bacteria and fungi. However, the mechanism by which riboflavin regulates seed development is poorly understood. Here, we report a novel maize (Zea mays L.) opaque mutant o18, which displays an increase in lysine accumulation, but impaired endosperm filling and embryo development. O18 encodes a rate-limiting bifunctional enzyme ZmRIBA1, targeted to plastid where to initiate riboflavin biosynthesis. Loss of function of O18 specifically disrupts respiratory complexes I and II, but also decreases SDH1 flavinylation, and in turn shifts the mitochondrial tricarboxylic acid (TCA) cycle to glycolysis. The deprivation of cellular energy leads to cell-cycle arrest at G1 and S phases in both mitosis and endoreduplication during endosperm development. The unexpected up-regulation of cell-cycle genes in o18 correlates with the increase of H3K4me3 levels, revealing a possible H3K4me-mediated epigenetic back-up mechanism for cell-cycle progression under unfavourable circumstances. Overexpression of O18 increases riboflavin production and confers osmotic tolerance. Altogether, our results substantiate a key role of riboflavin in coordinating cellular energy and cell cycle to modulate maize endosperm development.

Effects of Acute Exposure to 3500 MHz (5G) Radiofrequency Electromagnetic Radiation on Anxiety-Like Behavior and the Auditory Cortex in Guinea Pigs.

Numerous studies have shown that radiofrequency electromagnetic radiation (RF-EMR) may negatively affect human health. We detected the effect of 3500 MHz RF-EMR on anxiety-like behavior and the auditory cortex (ACx) in guinea pigs. Forty male guinea pigs were randomly divided into four groups and exposed to a continuous wave of 3500 MHz RF-EMF at an average specific absorption rate (SAR) of 0, 2, 4, or 10 W/kg for 72 h. After exposure, malondialdehyde (MDA) levels, antioxidant enzyme activity, anxiety-like behavior, hearing thresholds, cell ultrastructure, and apoptosis were detected. Our results revealed that hearing thresholds and basic indexes of animal behavior did not change significantly after exposure (P > 0.05). However, the MDA levels of ACx were increased (P < 0.05), and catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) activities were decreased (P < 0.05) in the exposure groups compared to the sham group. Ultrastructural changes of ACx, including swollen mitochondria and layered myelin sheaths, were observed. Cytochrome-c relocalization, caspase-9, and cleaved caspase-3 activation were detected in the exposure groups. In conclusion, these results suggest that oxidative stress is an important mechanism underlying the biological effects of RF-EMR, which can induce ultrastructural damage to the ACx and cell apoptosis through a mitochondria-dependent mechanism. Moreover, oxidative stress, apoptosis induction and ultrastructural damage increase in a SAR-dependent manner. However, RF-EMR does not increase hearing thresholds or induce anxiety. Bioelectromagnetics. 43:106-118, 2022. © 2021 Bioelectromagnetics Society.

Nursing Care Plan and Management of Patients With Acute Leukemia.

OBJECTIVE: To provide an overview of the integration of nursing care services for patients with acute leukemia in the past, present and future. DATA SOURCES: Published literature as indexed in Medline, relevant guideline documents, textbooks and clinical experience. CONCLUSION: Patients with acute leukemia have significant nursing care demands that are frequently unmet by routine oncology treatment. The initial introduction of expert nursing care into routine oncology treatment boosts patient-centered results in people with advanced solid tumors, according to research. Recent data suggest that patients with hematologic malignancies who have undergone transplantation of stem cells have similarly improved, and further trials are being conducted to assess nursing care treatments in patients with acute leukemia. NURSING PRACTICE IMPLICATIONS: Nurses are essential in the management of patients with acute leukemia both in and out of the hospital. As a result, having a basic understanding of these illnesses is critical. In the management of oncologic crises, early symptom identification is crucial.

Exposure to maternal diabetes induces endothelial dysfunction and hypertension in adult male rat offspring.

The adverse environment in early life can modulate adult phenotype, including blood pressure. Our previous study shows, in a rat streptozotocin (STZ)-induced maternal diabetes model, fetal exposure to maternal diabetes is characterized by established hypertension in the offspring. However, the exact mechanisms are not known. Our present study found, as compared with male control mother offspring (CMO), male diabetic mother offspring (DMO) had higher blood pressure with arterial dysfunction, i.e., decreased acetylcholine (Ach)-induced vasodilation. But there is no difference in blood pressure between female CMO and DMO. The decreased Ach-induced vasodilation was related to decreased nitric oxide (NO) production in the endothelium, not NO sensitivity in vascular smooth muscle because sodium nitroprusside (SNP)-mediated vasodilation was preserved; there was decreased NO production and lower eNOS phosphorylation in male DMO. The reactive oxygen species (ROS) level was increased in male DMO than CMO; normalized ROS levels with tempol increased NO production, normalized Ach-mediated vasodilation, and lowered blood pressure in male DMO rats. It indicates that diabetic programming hypertension is related to arterial dysfunction; normalizing ROS might be a potential strategy for the prevention of hypertension in the offspring.

Upregulation of TIGIT and PD-1 in Colorectal Cancer with Mismatch-repair Deficiency.

Background: The role of T cell Ig and ITIM domain (TIGIT) and programmed cell death-1 (PD-1) in colorectal cancer (CRC) with mismatch repair deficiency is unknown.Methods: This was a study of 60 CRC patients with mismatch repair deficiency and 30 healthy controls between June 2015 and October 2015.Results: The expression of Foxp3, PD-1, and TIGIT was higher in cancer tissues compared with adjacent mucosa (all P < .05). Patients with advanced TNM stage had a significantly higher expression of TIGIT (P = .025) and PD-1 (P = .020) than patients with early-stage CRC. The disease-free survival (DFS) of patients with high TIGIT (HR = 3.96, 95%CI: 1.34-11.69, P = .013) or PD-1 (HR = 214.8, 95%CI: 49.88-925.2, P < .001) expression were better. The overall survival (OS) of the patients with CRC and high expression of PD-1 was worse than those with low expression (HR = 4.01, 95%CI:1.26-12.69, P = .019).Conclusion: TIGIT and PD-1 are upregulated in CRC with mismatch repair deficiency and associated with TNM stage and DFS.

An efficient imidation of thioethers with nitrene in water.

The first imidation of thioethers with free nitrene in water was realized. N-Cbz sulfilimines are formed via imidation of thioethers with free nitrene generated from α elimination of nosyloxycarbamates. In this work, water is successfully applied as solvent for free nitrene, and transition metal catalyst is not needed.

Diagnostic Potential for Circular RNAs in Gastric Carcinoma: a Meta-Analysis.

BACKGROUND: Circular RNAs (circRNAs) are potential, novel biomarkers for the early diagnosis of gastric carcinoma. Herein, a meta-analysis was conducted to assess the diagnostic potential for circRNAs in gastric carcinoma. METHODS: Online databases were searched for eligible studies. Study quality was judged using the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) checklist-II tool. STATA 12.0 and Meta-Disc 1.4 software were used for statistical analysis. RESULTS: Twelve studies consisting of 1,278 patients and 1,250 paired controls were considered for meta-analysis. The pooled sensitivity and specificity of circRNAs for gastric carcinoma were compared to normal controls and found to be 0.68 (95% CI: 0.66 - 0.71) and 0.70 (95% CI: 0.68 - 0.73), respectively. A corresponding area under the receiver operating characteristic curve of 0.78 was identified. Moreover, stratified analysis demonstrated an improved diagnostic value for circRNAs when tissue and plasma specimens were combined. CONCLUSIONS: This meta-analysis demonstrates that circRNAs are promising biomarkers for gastric carcinoma.

Epidemiology of Pediatric Severe Sepsis in Main PICU Centers in Southwest China.

OBJECTIVES: To estimate the prevalence, management, and outcomes of pediatric severe sepsis in the main PICUs in Southwest China. DESIGN: A prospective, observational, and multicenter study. SETTING: Eight PICUs in Southwest China with 19 (13-24) beds and 1,322 (1,066-1,452) annual admissions each. PATIENTS: A total of 10,598 patients (29 d to 18 yr old) were consecutively admitted between September 1, 2016, and August 31, 2017. All patients were screened and evaluated for severe sepsis or septic shock. Of them, 10,353 patients were excluded due to incomplete data or not meeting the consensus criteria for severe sepsis or septic shock; 245 patients were included with complete data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Finally, 245 patients who were diagnosed with severe sepsis or septic shock were included in the study, with an incidence rate of 2.3%. Of them, 64.0% of the enrolled patients were male with 80.8% being less than 5 years old and 60.8% being from rural areas. The respiratory system was the most common organ system in which dysfunction was observed (76.7%) as well as the most frequently infected site (37.6%). The primary therapies were antibiotics (99.0%), immunoglobulin (88.3%), mechanical ventilation (78.4%), vasoactive infusions (59.6%), and corticosteroids (46.1%). Among the 188 patients who had respiratory dysfunction, 173(92%) required mechanical ventilation and 39 (20.7%) met the criteria for pediatric acute respiratory distress syndrome. Seven of the patients with pediatric acute respiratory distress syndrome died (7/39, 17.9%). The median durations for mechanical ventilation and vasoactive medications were 123.5 hours (35.25-226.00 hr) and 2 days (1-5 d), respectively. Eighty-six percent of patients had multiple organ dysfunction syndrome at the point at which severe sepsis was recognized, and 31% had underlying conditions. The hospital mortality rate was 18.8%. CONCLUSIONS: This report is the first to present the prevalence, treatment, and outcomes of pediatric severe sepsis in the main PICU centers in Southwest China. The mortality rate remains high; therefore, improved clinical management and implementation of large-scale clinical trials are necessary to improve early diagnoses and treatment.

YaAn earthquake increases blood pressure among hospitalized patients.

BACKGROUND: YaAn, a city in Sichuan province, China, was struck by a major earthquake measuring 7.0 on the Richter scale on April 20, 2013. This study sought to investigate the impact of YaAn earthquake on the blood pressure (BP) among hospitalized patients in the department of cardiology. METHODS: We enrolled 52 hospitalized patients who were admitted to our hospital at least three days before the day of earthquake in 2013 (disaster group) as compared with 52 patients during April 20, 2014 (nondisaster group). BP was measured three times per day and the prescription of antihypertensive medicine was recorded. RESULTS: The earthquake induced a 3.3 mm Hg significant increase in the mean postdisaster systolic blood pressure (SBP) in the disaster group as compared with the nondisaster group. SBP at admission was positively associated with the elevated SBP in the logistic regression model (odds ratio (OR) = 1.09, 95% confidence interval (CI):1.016-1.168, p = 0.015), but not other potential influencing factors, including antihypertensive medicine, sex, age, and body weight, excluding ß-blockers. Patients with ß-blockers prescription at the time of earthquake showed a blunt response to earthquake-induced SBP elevation than those who were taking other antihypertensive drugs (OR = 0.128, 95% CI: 0.019-0.876, p = 0.036). CONCLUSION: The YaAn earthquake induced significant increase in SBP even at a distance from the epicenter among hospitalized patients. The findings demonstrate that pure psychological components seem to be a cause of the pressor response and ß-blockers might be better in controlling disaster-induced hypertension.

Elevated plasma levels of specific antiplatelet glycoprotein autoantibodies in patients with primary Sjögren syndrome with thrombocytopenia.

INTRODUCTION: Thrombocytopenia is one of the primary Sjögren's syndrome (pSS) hematological manifestations. The objective of this study was to evaluate the possible roles of antiplatelet glycoprotein autoantibodies in the pathogenesis of thrombocytopenia in primary Sjögren's syndrome (pSS). METHODS: The level of plasma anti-glycoprotein Ib, IIIa and IIb/IIIa autoantibodies in 36 pSS patients without thrombocytopenia and 35 pSS patients with thrombocytopenia, 36 Idiopathic thrombocytopenic purpura (ITP) patients and 39 normal control were measured with enzyme-linked immunosorbent assay (ELISA). RESULTS: The level of anti-GPIb, GPIIIa, GPIIb/IIIa autoantibodies (A490) in the pSS with thrombocytopenia was significantly higher than that of pSS without thrombocytopenia (0.813 ± 0.161 vs 0.688 ± 0.133; 0.917 ± 0.094 vs 0.802 ± 0.070; 0.911 ± 0.125 vs 0.782 ± 0.109). Incidences of the anti-GPIb, GPIIIa, GPIIb/IIIa autoantibodies in the pSS with thrombocytopenia was significantly higher than that of pSS without thrombocytopenia (25.7% vs 0%; 65.7% vs 11.1%; 31.4% vs 0%). In patients with pSS, there was a lower platelet count in anti-GPIb, GPIIIa, GPIIb/IIIa autoantibodies positive patients ((25.67 ± 5.5) × 10^9/L vs (116.8 ± 84.52) × 10^9/L; 29.04 ± 11.33 × 10^9/L vs (152.0 ± 75.47) × 10^9/L; (31.55 ± 14.0) × 10^9/L vs (118.8 ± 85.24) × 10^9/L). CONCLUSION: Elevated plasma levels of anti-platelet glycoprotein autoantibodies may play a role in the pathogenesis of thrombocytopenia in pSS. Key Points • The level of anti-GPIb, GPIIIa, GPIIb/IIIa autoantibodies (A490) in the pSS with thrombocytopenia was increased. • Incidences of the anti-GPIb, GPIIIa, GPIIb/IIIa autoantibodies in the pSS with thrombocytopenia was increased. • In patients with pSS, there was a lower platelet count in anti-GPIb, GPIIIa, GPIIb/IIIa autoantibodies positive patients.

The chief culprit of intractable hypoxemia: a case report of rare pulmonary arteriovenous fistula complicated with giant hemangioma.

BACKGROUND: Pulmonary arteriovenous fistula (PAVF) is a rare disease, which can lead to the direct return of unoxidized venous blood to pulmonary veins and left heart, resulting in right-to-left shunt leading to hypoxia. Long term, the right-to-left shunt will cause severe pathophysiological changes in the patient's body and pulmonary circulation, and the prognosis will be poor if PAVF is not treated timely. CASE PRESENTATION: Here, we report the case of a 71-year-old man who presented with chest tightness and shortness of breath. After a series of examinations, PAVF and giant hemangioma were diagnosed, which are difficult to operate.Transcatheter interventional therapy was initiated. The patient recovered on the third day after operation and was discharged smoothly. During the long-term follow-up of nearly 4 years after discharge, the general condition and quality of life of the patient basically returned to normal. CONCLUSIONS: PAVF is rare but very important clinical problem. When the clinical manifestations of persistent unexplained hypoxia appear, it is necessary to fully consider the possibility of PAVF. Once the diagnosis of PAVF is clear, timely treatment is recommended to avoid deterioration of the disease and affecting the prognosis.

Laryngopharyngeal Reflux and Benign Vocal Fold Lesions: A Systematic Review and Meta-analysis.

OBJECTIVE: There is a link between laryngopharyngeal reflux (LPR) and the formation of benign vocal fold lesions (BVFLs). However, previous studies have mainly focused on LPR suggested by symptoms and signs, rather than objectively diagnosed LPR via pharyngeal pH monitoring. We, therefore, conducted a Meta-analysis to evaluate the association between pharyngeal pH monitoring diagnosed LPR and the odds of BVFLs. DATA SOURCES: Relevant observational studies were identified by searching PubMed, Embase, Cochrane Library, and Web of Science. REVIEW METHODS: We evaluated between-study heterogeneity using the Cochrane Q test and estimated the I2 statistic. Random-effects models were used when significant heterogeneity was observed; otherwise, fixed-effects models were used. RESULTS: Thirteen datasets from 9 studies were included. Among them, 493 were diagnosed with LPR and 344 had BVFLs. LPR was related to a higher odds of BVFLs (odds ratio: 3.26, 95% confidence interval: 1.84-5.76, P < .001) with moderate heterogeneity (P for Cochrane Q test = .006, I2 = 57%). Subgroup analyses showed that the association was similar in studies with only pharyngeal pH monitoring (Restech), with double-probe or 3-site pH monitoring, and with 24-hour multichannel intraluminal impedance-pH monitoring (P for subgroup difference = .15). In addition, subgroup analysis showed consistent results in studies from Asia and Europe (P for subgroup analysis = .12), and the association seemed to be consistent for vocal Reinke's edema, nodules, and polyps (P for subgroup difference = .09). CONCLUSION: Pharyngeal pH monitoring diagnosed LPR is associated with the formation of BVFLs.

Failure of lipid control by PCSK9 inhibitors in compound heterozygous familial hypercholesterolemia complicated with premature myocardial infarction: A case report.

Key Clinical Message: A certain level of low-density lipoprotein receptor activity is crucial for the efficacy of PCSK9i. Therapeutic strategies for familial hypercholesterolemia patients should consider drug efficacy, and genetic testing will be helpful. Abstract: Familial hypercholesterolemia (FH) is a serious autosomal dominant disorder. Managing blood lipids in FH patients poses greater challenges for clinicians. Drug therapy may not always yield satisfactory results, particularly in individuals with low-density lipoprotein receptor (LDLR) negative mutations. Herein, we report a young female harboring an LDLR frameshift mutation. This patient developed xanthomas at 7 months old and underwent several years of treatment involving four classes of lipid-lowering drugs, including PCSK9i. However, the response to drug therapy was limited in this patient and eventually culminated in premature myocardial infarction. The efficacy of PCSK9i depends on the activity of LDLR. The inefficacy of PCSK9i may arise from the extensive mutations which leading to loss of LDLR activity. Therapy plans for these patients should take into account the efficacy of drug therapy. Early genetic testing is crucial for clinicians to make informed decisions regarding therapy options.

HydrogelFinder: A Foundation Model for Efficient Self-Assembling Peptide Discovery Guided by Non-Peptidal Small Molecules.

Self-assembling peptides have numerous applications in medicine, food chemistry, and nanotechnology. However, their discovery has traditionally been serendipitous rather than driven by rational design. Here, HydrogelFinder, a foundation model is developed for the rational design of self-assembling peptides from scratch. This model explores the self-assembly properties by molecular structure, leveraging 1,377 self-assembling non-peptidal small molecules to navigate chemical space and improve structural diversity. Utilizing HydrogelFinder, 111 peptide candidates are generated and synthesized 17 peptides, subsequently experimentally validating the self-assembly and biophysical characteristics of nine peptides ranging from 1-10 amino acids-all achieved within a 19-day workflow. Notably, the two de novo-designed self-assembling peptides demonstrated low cytotoxicity and biocompatibility, as confirmed by live/dead assays. This work highlights the capacity of HydrogelFinder to diversify the design of self-assembling peptides through non-peptidal small molecules, offering a powerful toolkit and paradigm for future peptide discovery endeavors.

Aldosterone inhibits Dot1l expression in guinea pig cochlea.

BACKGROUND: Aldosterone relieves transcriptional repression of epithelial sodium channel (ENaC) by inhibiting Dot1a and Af9 expression and their interaction with ENaC promoter in various tissues. Expressions of ENaC and Af9 in inner ear have been identified. However, it is not known how Dot1l is regulated by aldosterone in inner ear. METHODS: Twenty-eight adult guinea pigs were randomly divided into the control group and treatment group. Aldosterone 1 mg/kg/d was injected intraperitoneally in the treatment group and saline in the control group for 7 days. Animals were killed 1 month later following auditory brainstem response examination. Histomorphology of cochlea was detected with hematoxylin-eosin staining, and Dot1l expression was examined with immunohistochemistry and Western blot. RESULTS: There was no significant difference in ABR thresholds before and after injection of aldosterone or saline in either group. Endolymphatic hydrops was found in 75% of animals in the treatment group. Dot1l was found in both groups in the stria vascularis, Reissner's membrane, spiral limbus, organ of Corti and spiral ligament. Dot1l expression in the treatment group was decreased by aldosterone. CONCLUSIONS: Dot1l in guinea pig cochlea is inhibited by aldosterone with induction of endolymphatic hydrops. Dot1l may be closely related to endolymph regulation by aldosterone and to pathogenesis of Meniere's disease.