Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis.

Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

Tyrosine kinase inhibitors for radioiodine refractory differentiated thyroid cancer: A systematic review and meta-analysis.

BACKGROUND: The poor overall prognosis of radioiodine refractory thyroid cancer is an inevitable challenge in managing this disease. A series of trials have demonstrated the antitumor activity of tyrosine kinase inhibitors (TKIs) in radioiodine refractory differentiated thyroid cancer (RAIR-DTC). However, the available evidence cannot determine the optimal choice of TKI in RAIR-DTC. METHODS: This study searched PubMed, EMBASE, Cochrane databases, and the ClinicalTrials website. The Cochrane bias risk tool was used to assess the risk of bias, and to evaluate randomized clinical trials (RCT) of RAIR-DTC patients treated with the TKI system. Outcomes, including progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were reported. RESULTS: Seven studies involving 1310 patients with RAIR-DTC was conducted to compare the PFS and OS of various TKI monotherapies with placebo. The results showed that all TKI monotherapies had a statistically significant benefit in terms of PFS compared with placebo, with lenvatinib demonstrating the greatest benefit (hazard ratio [HR] 0.19, 95% credible interval [CrI] 0.14-0.25). In terms of OS, only apatinib (HR 0.42, 95% CrI 0.18-0.97) and anlotinib (HR 0.36, 95% CrI 0.18-0.73) showed statistically significant benefits compared with placebo. TKIs also had a higher incidence of AEs of grade 3 or higher compared with placebo. The findings suggest that lenvatinib may be the preferred TKI for the treatment of RAIR-DTC, although its high incidence of AEs should be considered. The results also indicate that TKI treatment may be similarly effective in RAIR-DTC patients with BRAF or RAS mutations and in those with papillary or follicular subtypes of the disease, regardless of prior TKI treatment. CONCLUSIONS: The results of this meta-analysis suggest that targeted therapy with TKIs may be beneficial for patients with radioiodine-refractory advanced or metastatic differentiated thyroid cancer. Among the TKIs analyzed, lenvatinib appeared to be the most effective at improving PFS, although it also had the highest incidence of AEs. Further research through direct randomized controlled trials is needed to determine the optimal choice of TKI for treating patients with RAIR-DTC. This study is beneficial for formulating patients' treatment plans and guides clinicians' decision-making.

An Integrated Clinical and Computerized Tomography-Based Radiomic Feature Model to Separate Benign from Malignant Pleural Effusion.

INTRODUCTION: Distinguishing between malignant pleural effusion (MPE) and benign pleural effusion (BPE) poses a challenge in clinical practice. We aimed to construct and validate a combined model integrating radiomic features and clinical factors using computerized tomography (CT) images to differentiate between MPE and BPE. METHODS: A retrospective inclusion of 315 patients with pleural effusion (PE) was conducted in this study (training cohort: n = 220; test cohort: n = 95). Radiomic features were extracted from CT images, and the dimensionality reduction and selection processes were carried out to obtain the optimal radiomic features. Logistic regression (LR), support vector machine (SVM), and random forest were employed to construct radiomic models. LR analyses were utilized to identify independent clinical risk factors to develop a clinical model. The combined model was created by integrating the optimal radiomic features with the independent clinical predictive factors. The discriminative ability of each model was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). RESULTS: Out of the total 1,834 radiomic features extracted, 15 optimal radiomic features explicitly related to MPE were picked to develop the radiomic model. Among the radiomic models, the SVM model demonstrated the highest predictive performance [area under the curve (AUC), training cohort: 0.876, test cohort: 0.774]. Six clinically independent predictive factors, including age, effusion laterality, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 125 (CA125), and neuron-specific enolase (NSE), were selected for constructing the clinical model. The combined model (AUC: 0.932, 0.870) exhibited superior discriminative performance in the training and test cohorts compared to the clinical model (AUC: 0.850, 0.820) and the radiomic model (AUC: 0.876, 0.774). The calibration curves and DCA further confirmed the practicality of the combined model. CONCLUSION: This study presented the development and validation of a combined model for distinguishing MPE and BPE. The combined model was a powerful tool for assisting in the clinical diagnosis of PE patients.

Empagliflozin ameliorates the impaired osteogenic differentiation ability of adipose-derived stem cells in diabetic osteoporosis by activating autophagy.

Adipose-derived stem cells (ASCs) from diabetic osteoporosis (DOP) mice showed impaired osteogenic differentiation capacity. Recent studies have shown that in addition to antidiabetic drugs, sodium-glucose co-transporter inhibitor-2 (SGLT-2), empagliflozin, can play multipotent roles through various mechanisms of action. In this study, we aimed to investigate the effects and underlying mechanisms of empagliflozin on osteogenic differentiation of ASCs in DOP mice. Our results showed that osteogenic differentiation potential and autophagy activity weakened in DOP-ASCs when compared to controls. However, empagliflozin enhanced autophagy flux by promoting the formation of autophagosomes and acidification of autophagic lysosomes, resulting in an increase in LC3-II expression and a decrease in SQSTM1 expression. Furthermore, empagliflozin contributed to the reversal of osteogenesis inhibition in DOP-ASCs induced by a diabetic microenvironment. When 3-methyladenine was used to block autophagy activity, empagliflozin could not exert its protective effect on DOP-ASCs. Nonetheless, this study demonstrated that the advent of cellular autophagy attributed to the administration of empagliflozin could ameliorate the impaired osteogenic differentiation potential of ASCs in DOP mice. This finding might be conducive to the application of ASCs transplantation for promoting bone fracture healing and bone regeneration in DOP patients.

Pet safety guidelines for pediatric transplant recipients.

Approximately 70% (90.5 million) of United States (US) households own at least one pet. Dogs are the most common, making up about 38% of all household pets, followed by cats, which make up 25%. Other pets such as fish, birds, reptiles, and small animals such as hamsters, gerbils, and rabbits are less common household members. Pets are often considered a part of the family and there are significant medical and psychosocial benefits to pet ownership; however, the possibility of disease transmission exists related to the type of animal and infectious organism, and specific human risk factors. Immunocompromised individuals may be at increased risk of serious illness from zoonotic infections. During the transplant evaluation and routinely posttransplant, the multidisciplinary team should inquire about pet ownership and animal exposures to guide on potential risks. This review discusses the most common diseases seen in various household pets including dogs, cats, birds, fish, and some farm animals. We will also present guidelines for pet safety and include strategies to decrease the risk of infection while supporting the benefits of pet ownership after transplant.

An α-hemoglobin-derived peptide (m)VD-hemopressin (α) promotes NREM sleep via the CB1 cannabinoid receptor.

Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. The previous studies demonstrated that the endocannabinoid system played important roles in modulating several physiological functions such as sleep, olfaction, emotion, learning and memory, and reward behaviors. Mouse VD-hemopressin (α) [(m)VD-HPα], an 11-residue peptide derived from the α1 chain of hemoglobin, was recently presumed as a selective agonist of the CB1 receptor. The present study was undertaken to investigate the effects of (m)VD-HPα on the sleep-wake cycle and power spectrum of cortical EEG in freely moving rats and the potential neurons in the brain activated by (m)VD-HPα. The results showed that 20.1 nmol of (m)VD-HPα i.c.v. administration increased non-rapid eye movement (NREM) sleep in the first 2 h section accompanied by an increase in EEG delta (0.5-4 Hz) activity. The (m)VD-HPα-induced NREM sleep enhancement was due to extended episode duration instead of the episode number. In addition, the effect of (m)VD-HPα (20.1 nmol) on sleep-wake states was significantly attenuated by an antagonist of the CB1 receptor, AM251 (20 nmol, i.c.v.) but not by the CB2 receptor antagonist, AM630 (20 nmol, i.c.v.). In comparison with vehicle, (m)VD-HPα increased Fos-immunoreactive (-ir) neurons in the ventrolateral preoptic nucleus (VLPO), but reduced Fos-ir neurons in the lateral hypothalamus (LH), tuberomammillary nucleus (TMN), and locus coeruleus (LC). These findings suggest that (m)VD-HPα promotes NREM sleep via the CB1 cannabinoid receptor to probably activate VLPO GABAergic neurons, but inactivates the LH orexinergic, LC noradrenergic, and TMN histaminergic neurons.

Association of Dietary Potassium Intake With Abdominal Aortic Calcification and Pulse Pressure in US Adults.

OBJECTIVES: Arterial calcification contributes to cardiovascular mortality. Based on a recent animal study, we hypothesized that higher dietary potassium intake was associated with less abdominal aortic calcification (AAC) and lower arterial stiffness among adults in the United States. METHODS: Cross-sectional analyses were performed on participants over 40 years old from the National Health and Nutrition Examination Survey 2013-2014. Dietary potassium intake was categorized into quartiles (Q1: <1911, Q2: 1911-2461, Q3: 2462-3119, and Q4: >3119 mg/d). Primary outcome AAC was quantified using the Kauppila scoring system. AAC scores were categorized into no AAC (AAC = 0, reference group), mild/moderate (AAC >0 to ≤ 6), and severe AAC (AAC >6). Pulse pressure was used as a surrogate for arterial stiffness and examined as a secondary outcome. RESULTS: Among 2,418 participants, there was not a linear association between dietary potassium intake and AAC. Higher dietary potassium intake was associated with less severe AAC when comparing dietary potassium intake in Q2 with Q1 (odds ratio 0.55; 95% confidence interval: 0.34 to 0.92; P = .03). Higher dietary potassium intake was significantly associated with lower pulse pressure (P = .007): per 1000 mg/d higher dietary potassium intake, pulse pressure was 1.47 mmHg lower in the fully adjusted model. Compared to participants with dietary potassium intake in Q1, pulse pressure was 2.84 mmHg lower in Q4 (P = .04). CONCLUSIONS: We did not find a linear association between dietary potassium intake and AAC. Dietary potassium intake was negatively associated with pulse pressure.

Peripheral changes in T cells predict efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer.

The application of programmed cell death protein 1 (PD-1) antibodies has brought great benefits to non-small cell lung cancer (NSCLC) patients. Nevertheless, not all patients respond to anti-PD-1 immunotherapy. This study aimed to find response markers to predict efficacy of anti-PD-1 immunotherapy in NSCLC patients. 80 patients with NSCLC who would accept anti-PD-1 immunotherapy were recruited, and peripheral blood was obtained before and after treatment. Flow cytometry was used to detect proportions of circulating cell subsets and expression of co-stimulatory molecules, co-inhibitory molecules and cytokines in T cells from pre- and post-treatment patients. Results showed that proportions of CD4+ and CD8+ T cells, NK, γδT and mucosal-associated invariant T (MAIT) cells were higher and regulatory T cells (Tregs) were lower in responders (n = 50) after treatment but no obvious difference was found in non-responders (n = 30). After treatment, responders showed an increase in the frequency of co-stimulatory and co-inhibitory molecules, as well as the production of cytokines in T cells. This study indicates that monitoring the alterations of immune markers in circulating cells from NSCLC patients may be helpful to discriminate responders and non-responders, which provides a potential novel way to assess efficacy of anti-PD-1 immunotherapy.

Hydrogel Drug Delivery Systems for Bone Regeneration.

With the in-depth understanding of bone regeneration mechanisms and the development of bone tissue engineering, a variety of scaffold carrier materials with desirable physicochemical properties and biological functions have recently emerged in the field of bone regeneration. Hydrogels are being increasingly used in the field of bone regeneration and tissue engineering because of their biocompatibility, unique swelling properties, and relative ease of fabrication. Hydrogel drug delivery systems comprise cells, cytokines, an extracellular matrix, and small molecule nucleotides, which have different properties depending on their chemical or physical cross-linking. Additionally, hydrogels can be designed for different types of drug delivery for specific applications. In this paper, we summarize recent research in the field of bone regeneration using hydrogels as delivery carriers, detail the application of hydrogels in bone defect diseases and their mechanisms, and discuss future research directions of hydrogel drug delivery systems in bone tissue engineering.

The association of low birthweight and prematurity on outcomes in children and adults with nephrotic syndrome-a NEPTUNE cohort study.

BACKGROUND: In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity). METHODS: Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes. RESULTS: We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth. CONCLUSION: LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.

Application of Nucleic Acid Nanomaterials in the Treatment of Endocrine and Metabolic Diseases.

Endocrine and metabolic diseases are the most prevalent chronic diseases globally, posing the greatest hazard to human health. Although various medications are applied in treating endocrine and metabolic illnesses, numerous obstacles exist to overcome. Nucleic acid nanomaterials are novel materials synthesized and engineered in the laboratory. In this case, Nucleic acids are employed as non-biological nanomaterials instead of serving as carriers of genetic information in live cells. Because of their high biocompatibility and editability, nucleic acid nanomaterials were frequently employed in disease diagnosis and therapy. In this review, recent developments and new viewpoints on nucleic acid nanomaterials are highlighted in the fields of diabetes mellitus and other endocrine and metabolic diseases.

Function of stem cells in radiation-induced damage.

PURPOSE: The aim of this review is to discuss previous studies on the function of stem cells in radiation-induced damage, and the factors affecting these processes, in the hope of improving our understanding of the different stem cells and the communication networks surrounding them. This is essential for the development of effective stem cell-based therapies to regenerate or replace normal tissues damaged by radiation. CONCLUSION: In salivary glands, senescence-associated cytokines and inflammation-associated cells have a greater effect on stem cells. In the intestinal glands, Paneth cells strongly affect stem cell-mediated tissue regeneration after radiation treatment. In the pancreas, ß-cells as well as protein C receptor positive (Procr) cells are expected to be key cells in the treatment of diabetes. In the bone marrow, a variety of cytokines such as CXC-chemokine ligand 12 (CXCL12) and stem cell factor (SCF), contribute to the functional recovery of hematopoietic stem cells after irradiation.

Causal association between obesity and hypothyroidism: a two-sample bidirectional Mendelian randomization study.

Introduction: Previous observational studies have reported a positive correlation between obesity and susceptibility to hypothyroidism; however, there is limited evidence from alternative methodologies to establish a causal link. Methods: We investigated the causal relationship between obesity and hypothyroidism using a two-sample bidirectional Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms (SNPs) associated with obesity-related traits were extracted from a published genome-wide association study (GWAS) of European individuals. Summarized diagnostic data of hypothyroidism were obtained from the UK Biobank. Primary analyses were conducted using the inverse variance-weighted (IVW) method with a random-effects model as well as three complementary approaches. Sensitivity analyses were performed to ascertain the correlation between obesity and hypothyroidism. Results: MR analyses of the IVW method and the analyses of hypothyroidism/myxedema indicated that body mass index (BMI) and waist circumference (WC) were significantly associated with higher odds and risk of hypothyroidism. Reverse MR analysis demonstrated that a genetic predisposition to hypothyroidism was associated with an increased risk of elevated BMI and WC, which was not observed between WC adjusted for BMI (WCadjBMI) and hypothyroidism. Discussion: Our current study indicates that obesity is a risk factor for hypothyroidism, suggesting that individuals with higher BMI/WC have an increased risk of developing hypothyroidism and indicating the importance of weight loss in reducing the risk of hypothyroidism.

Rapid Eye Movement Sleep during Early Life: A Comprehensive Narrative Review.

The ontogenetic sleep hypothesis suggested that rapid eye movement (REM) sleep is ontogenetically primitive. Namely, REM sleep plays an imperative role in the maturation of the central nervous system. In coincidence with a rapidly developing brain during the early period of life, a remarkably large amount of REM sleep has been identified in numerous behavioral and polysomnographic studies across species. The abundant REM sleep appears to serve to optimize a cerebral state suitable for homeostasis and inherent neuronal activities favorable to brain maturation, ranging from neuronal differentiation, migration, and myelination to synaptic formation and elimination. Progressively more studies in Mammalia have provided the underlying mechanisms involved in some REM sleep-related disorders (e.g., narcolepsy, autism, attention deficit hyperactivity disorder (ADHD)). We summarize the remarkable alterations of polysomnographic, behavioral, and physiological characteristics in humans and Mammalia. Through a comprehensive review, we offer a hybrid of animal and human findings, demonstrating that early-life REM sleep disturbances constitute a common feature of many neurodevelopmental disorders. Our review may assist and promote investigations of the underlying mechanisms, functions, and neurodevelopmental diseases involved in REM sleep during early life.

Stereotaxic atlas of the infant rat brain at postnatal days 7-13.

Recently, researchers have paid progressively more attention to the study of neural development in infant rats. However, due to the lack of complete intracerebral localization information, such as clear nuclear cluster boundaries, identified main brain structures, and reliable stereotaxic coordinates, it is difficult and restricted to apply technical neuroscience to infant rat's brain. The present study was undertaken to refine the atlas of infant rats. As such, we established a stereotaxic atlas of the infant rat's brain at postnatal days 7-13. Furthermore, dye calibration surgery was performed in P7-P13 infant rats by injecting Methylene blue, and sections were incubated in Nissl solutions. From the panoramic images of the brain sections, atlases were made. Our article has provided the appearance and measurements of P7-P13 Sprague-Dawley rat pups. Whereas the atlas contains a series of about 530 coronal brain section images from olfactory bulbs to the brainstem, a list of abbreviations of the main brain structures, and reliable stereotaxic coordinates, which were demonstrated by vertical and oblique injections with fluorescent dye DiI. The present findings demonstrated that our study of P7-P13 atlases has reasonable nucleus boundaries and accurate and good repeatability of stereotaxic coordinates, which can make up for the shortage of postnatal rat brain atlas currently in the field.

Mass spectrometry-based ganglioside profiling provides potential insights into Alzheimer's disease development.

Gangliosides are a family of glycosphingolipids which are particularly enriched in the nervous system. They play crucial roles in neuroprotection and neurological diseases. Alzheimer's disease (AD) is a neurodegenerative disease with cognitive, judgment and memory dysfunction. In this study, a mass spectrometry-based data-dependent acquisition method assisted with fragmentation characteristics screening by computer algorithm was developed for qualitative and quantitative analysis of gangliosides at low concentration. The developed method was applied to obtain detailed ganglioside species content in hippocampus of model mice (APPswe/PS1dE9 transgenic mice) with AD at 3- to 8-month-old. Up-regulated acetylated and N-acetylgalactosaminylated ganglioside species, and the down-regulated major gangliosides were observed with the development of AD from early to late stage. We speculated that deterioration of AD may be related to the acetylation/N-acetylgalactosaminylation transformation of complex gangliosides due to the inhibition of GD3 synthase activity. Moreover, the ganglioside species di-O-Ac-GT1a (d36:1), O-Ac-GD1b (d36:1) and O-Ac-GD1b (d36:0) were considered as the time-coursed biomarkers, and O-Ac-GT1a (d36:2) could be a candidate for early diagnosis of AD.

Effect of Preheating Temperature on Geometry and Mechanical Properties of Laser Cladding-Based Stellite 6/WC Coating.

The effect of 60Si2Mn substrate preheating on the forming quality and mechanical properties of cobalt-based tungsten carbide composite coating was investigated. Substrate preheating was divided into four classes (room temperature, 150 °C, 250 °C, and 350 °C). The morphology, microstructure, and distribution of elements of the coating were analyzed using a two-color laser handheld 3D scanner, a scanning electron microscope (SEM), and an energy dispersive X-ray spectrometer (EDX), respectively. The hardness and wear properties of the cladding layer were characterized through a microhardness tester and a friction wear experiment. The research results show that the substrate preheating temperature is directly proportional to the height of the composite coating. The solidification characteristics of the Stellite 6/WC cladding layer structure are not obviously changed at substrate preheating temperatures of room temperature, 150 °C, and 250 °C. The solidified structure is even more complex at a substrate preheating temperature of 350 °C. At this moment, the microstructure of the cladding layer is mainly various blocky, petaloid, and flower-like precipitates. The hardness and wear properties of the cladding layer are optimal at a substrate preheating temperature of 350 °C in terms of mechanical properties.