A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.

Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.

STRAS:a snakemake pipeline for genome-wide short tandem repeats annotation and score.

High-throughput whole genome sequencing (WGS) is clinically used in finding single nucleotide variants and small indels. Several bioinformatics tools are developed to call short tandem repeats (STRs) copy numbers from WGS data, such as ExpansionHunter denovo, GangSTR and HipSTR. However, expansion disorders are rare and it is hard to find candidate expansions in single patient sequencing data with ~ 800,000 STRs calls. In this paper I describe a snakemake pipeline for genome-wide STRs Annotation and Score (STRAS) using a Random Forest (RF) model to predict pathogenicity. The predictor was validated by benchmark data from Clinvar and PUBMED. True positive rate was 93.8%. True negative rate was 98.0%.Precision was 98.6% and recall rate was 93.8%. F1-score was 0.961. Sensitivity was 93.8% and specificity was 99.6%. These results showed STRAS could be a useful tool for clinical researchers to find STR loci of interest and filter out neutral STRs. STRAS is freely available at https://github.com/fancheyu5/STRAS .

Genome-wide association studies reveal novel loci for grain size in two-rowed barley (Hordeum vulgare L.).

KEY MESSAGE: SNP-based and InDel-based GWAS on multi-environment data identified genomic regions associated with barley grain size. Barley yield and quality are greatly influenced by grain size. Improving barley grain size in breeding programs requires knowledge of genetic loci and alleles in germplasm resources. In this study, a collection of 334 worldwide two-rowed barley accessions with extensive genetic diversity was evaluated for grain size including grain length (GL), grain width (GW), and thousand-grain weight (TGW) across six independent field trials. Significant differences were observed in genotype and environments for all measured traits. SNP- and InDel-based GWAS were applied to dissect the genetic architecture of grain size with an SLAF-seq strategy. Two approaches using the FarmCPU model revealed 38 significant marker-trait associations (MTAs) with PVE ranging from 0.01% to 20.68%. Among these MTAs, five were on genomic regions where no previously reported QTL for grain size. Superior alleles of TGW-associated SNP233060 and GL-associated InDel11006 exhibited significantly higher levels of phenotype. The significant MTAs could be used in marker-assisted selection breeding.

Predicting Two-Photon Absorption Spectra of Octupolar Molecules: A Deep-Learning Approach Based Exclusively on Molecular Structures.

Octupolar molecules possessing a strong two-photon response are vital for numerous advanced applications. However, accurately predicting their two-photon absorption (TPA) spectra requires high-precision quantum chemical calculations, which are computationally expensive due to repeated simulations of molecular excited-state properties. To address this challenge, we introduce a deep learning approach capable of rapidly and accurately forecasting TPA spectra for octupolar molecules. By leveraging the geometric structure as an initial descriptor, we employ a graph neural network to predict the maximum two-photon transition wavelength and cross-section. Our model demonstrates a mean absolute percentage error of less than 4% compared to time-dependent density-functional theory calculations, effectively reproducing experimental observations. Notably, this deep learning technique is nearly 100 000 times faster than comparable quantum calculations, making it an efficient and cost-effective tool for simulating TPA properties of octupolar molecules. Furthermore, this method holds great promise for the high-throughput screening of exceptional TPA materials.

Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported Lipid Bilayers as Targeted Delivery Vehicles.

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.

Famotidine Enhances Rifampicin Activity against Acinetobacter baumannii by Affecting OmpA.

The development of novel antibiotic adjuvants is imminent because of the frequent emergence of resistance in Gram-negative bacteria, which severely restricts the efficiency and longevity of commonly used clinical antibiotics. It is reported that famotidine, a clinical inhibitor of gastric acid secretion, enhances the antibacterial activity of rifamycin antibiotics, especially rifampicin, against Gram-negative bacteria and reverses drug resistance. Studies have shown that famotidine disrupts the cell membrane of Acinetobacter baumannii and inhibits the expression of the outer membrane protein ompA gene, while causing a dissipation of the plasma membrane potential, compensatively upregulating the pH gradient and ultimately increasing the accumulation of reactive oxygen species by leading to increased bacterial mortality. In addition, famotidine also inhibited the efflux pump activity and the biofilm formation of A. baumannii. In the Galleria mellonella and mouse infection models, the combination of famotidine and rifampicin increased the survival rate of infected animals and decreased the bacterial load in mouse organs. In conclusion, famotidine has the potential to be a novel rifampicin adjuvant, providing a new option for the treatment of clinical Gram-negative bacterial infections. IMPORTANCE In this study, famotidine was discovered for the first time to have potential as an antibiotic adjuvant, enhancing the antibacterial activity of rifamycin antibiotics against A. baumannii and overcoming the limitations of drug therapy. With the discovery of novel applications for the guanidine-containing medication famotidine, the viability of screening prospective antibiotic adjuvants from guanidine-based molecules was further explored. In addition, famotidine exerts activity by affecting the OmpA protein of the cell membrane, indicating that this protein might be used as a therapeutic drug target to treat A. baumannii infections.

Molecular insights into the responses of barley to yellow mosaic disease through transcriptome analysis.

BACKGROUND: Barley (Hordeum vulgare L.) represents the fourth most essential cereal crop in the world, vulnerable to barley yellow mosaic virus (BaYMV) and/or barley mild mosaic virus (BaMMV), leading to the significant yield reduction. To gain a better understanding of the mechanisms regarding barley crop tolerance to virus infection, we employed a transcriptome sequencing approach and investigated global gene expression among three barley varieties under both infected and control conditions. RESULTS: High-throughput sequencing outputs revealed massive genetic responses, reflected by the barley transcriptome after BaYMV and/or BaMMV infection. Significant enrichments in peptidase complex and protein processing in endoplasmic reticulum were clustered through Gene ontology and KEGG analysis. Many genes were identified as transcription factors, antioxidants, disease resistance genes and plant hormones and differentially expressed between infected and uninfected barley varieties. Importantly, general response genes, variety-specific and infection-specific genes were also discovered. Our results provide useful information for future barley breeding to resist BaYMV and BaMMV. CONCLUSIONS: Our study elucidates transcriptomic adaptations in barley response to BaYMV/BaMMV infection through high-throughput sequencing technique. The analysis outcome from GO and KEGG pathways suggests that BaYMV disease induced regulations in multiple molecular-biology processes and signalling pathways. Moreover, critical DEGs involved in defence and stress tolerance mechanisms were displayed. Further functional investigations focusing on these DEGs contributes to understanding the molecular mechanisms of plant response to BaYMV disease infection, thereby offering precious genetic resources for breeding barley varieties resistant to BaYMV disease.

HvNCX, a prime candidate gene for the novel qualitative locus qS7.1 associated with salinity tolerance in barley.

KEY MESSAGE: A major QTL (qS7.1) for salinity damage score and Na+ exclusion was identified on chromosome 7H from a barley population derived from a cross between a cultivated variety and a wild accession. qS7.1 was fine-mapped to a 2.46 Mb physical interval and HvNCX encoding a sodium/calcium exchanger is most likely the candidate gene. Soil salinity is one of the major abiotic stresses affecting crop yield. Developing salinity-tolerant varieties is critical for minimizing economic penalties caused by salinity and providing solutions for global food security. Many genes/QTL for salt tolerance have been reported in barley, but only a few of them have been cloned. In this study, a total of 163 doubled haploid lines from a cross between a cultivated barley variety Franklin and a wild barley accession TAM407227 were used to map QTL for salinity tolerance. Four significant QTL were identified for salinity damage scores. One (qS2.1) was located on 2H, determining 7.5% of the phenotypic variation. Two (qS5.1 and qS5.2) were located on 5H, determining 5.3-11.7% of the phenotypic variation. The most significant QTL was found on 7H, explaining 27.8% of the phenotypic variation. Two QTL for Na+ content in leaves under salinity stress were detected on chromosomes 1H (qNa1.1) and 7H(qNa7.1). qS7.1 was fine-mapped to a 2.46 Mb physical interval using F4 recombinant inbred lines. This region contains 23 high-confidence genes, with HvNCX which encodes a sodium/calcium exchanger being most likely the candidate gene. HvNCX was highly induced by salinity stress and showed a greater expression level in the sensitive parent. Multiple nucleotide substitutions and deletions/insertions in the promoter sequence of HvNCX were found between the two parents. cDNA sequencing of the HvNCX revealed that the difference between the two parents is conferred by a single Ala77/Pro77 amino acid substitution, which is located on the transmembrane domain. These findings open new prospects for improving salinity tolerance in barley by targeting a previously unexplored trait.

OCP002, a Mixed Agonist of Opioid and Cannabinoid Receptors, Produces Potent Antinociception With Minimized Side Effects.

BACKGROUND: Increasing attention has been attracted to the development of bifunctional compounds to minimize the side effects of opioid analgesics. Pharmacological studies have verified the functional interaction between opioid and cannabinoid systems in pain management, suggesting that coactivation of the opioid and cannabinoid receptors may provide synergistic analgesia with fewer adverse reactions. Herein, we developed and characterized a novel bifunctional compound containing the pharmacophores of the mu-opioid receptor agonist DALDA and the cannabinoid peptide VD-Hpα-NH2, named OCP002. METHODS: The opioid and cannabinoid agonistic activities of OCP002 were investigated in calcium mobilization and western blotting assays, respectively. Moreover, the central and peripheral antinociceptive effects of OCP002 were evaluated in mouse preclinical models of tail-flick test, carrageenan-induced inflammatory pain, and acetic acid-induced visceral pain, respectively. Furthermore, the potential opioid and cannabinoid side effects of OCP002 were systematically investigated in mice after intracerebroventricular (ICV) and subcutaneous (SC) administrations. RESULTS: OCP002 functioned as a mixed agonist toward mu-opioid, kappa-opioid, and cannabinoid CB1 receptors in vitro. ICV and SC injections of OCP002 produced dose-dependent antinociception in mouse models of nociceptive (the median effective dose [ED50] values with 95% confidence interval [CI] are 0.14 [0.12-0.15] nmol and 0.32 [0.29-0.35] µmol/kg for ICV and SC injections, respectively), inflammatory (mechanical stimulation: ED50 values [95% CI] are 0.76 [0.64-0.90] nmol and 1.23 [1.10-1.38] µmol/kg for ICV and SC injections, respectively; thermal stimulation: ED50 values [95% CI] are 0.13 [0.10-0.17] nmol and 0.23 [0.08-0.40] µmol/kg for ICV and SC injections, respectively), and visceral pain (ED50 values [95% CI] are 0.0069 [0.0050-0.0092] nmol and 1.47 [1.13-1.86] µmol/kg for ICV and SC injections, respectively) via opioid and cannabinoid receptors. Encouragingly, OCP002 cannot cross the blood-brain barrier and exerted nontolerance-forming analgesia over 6-day treatment at both supraspinal and peripheral levels. Consistent with these behavioral results, repeated OCP002 administration did not elicit microglial hypertrophy and proliferation, the typical features of opioid-induced tolerance, in the spinal cord. Furthermore, at the effective analgesic doses, SC OCP002 exhibited minimized opioid and cannabinoid side effects on motor performance, body temperature, gastric motility, physical and psychological dependence, as well as sedation in mice. CONCLUSIONS: This study demonstrates that OCP002 produces potent and nontolerance-forming antinociception in mice with reduced opioid- and cannabinoid-related side effects, which strengthen the candidacy of bifunctional drugs targeting opioid/cannabinoid receptors for translational-medical development to replace or assist the traditional opioid analgesics.

Two-sample Mendelian randomization study does not reveal a significant relationship between cytomegalovirus (CMV) infection and autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and impaired expressive communication. Cytomegalovirus (CMV) is considered a risk factor for ASD; however, published studies are usually limited by covering too few events and have different conclusions, indicating that the relationship between CMV infection and ASD remains elusive. METHODS: To investigate the association between CMV infection and ASD, we conducted this 2-sample Mendelian randomization (MR) study using genome-wide association studies (GWAS) summary data from FinnGen and the IEU Open GWAS project. RESULTS: Our results showed no significant relationship between all 3 CMV infections (unspecified cytomegaloviral diseases, anti-CMV IgG levels, and maternal CMV) and ASD. CONCLUSIONS: Our results indicate that CMV infection does not significantly increase ASD risk. These results show that the relationship between CMV infection and ASD remains elusive and needs to be further clarified.

The Impact of Consumer Wearable Devices on Physical Activity and Adherence to Physical Activity in Patients with Cardiovascular Disease: A Systematic Review of Systematic Reviews and Meta-Analyses.

Objective: Consumer wearable devices allow physical activity to be measured objectively, which can be useful in remote cardiovascular disease management. This review aimed to summarize the effects of using wearable devices to monitor physical activity/adherence to physical activity in adults with cardiovascular disease. Methods: The review used The Cochrane Overview of Reviews Methodology. The databases searched were PubMed, EMBASE, CINAHL, Web of Science, and the Cochrane Database of Systematic Reviews, the date of the last search was October 12, 2021. Risk of bias was assessed using the AMSTAR-2® tool. Results: Of the 767 records, we identified 6 systematic reviews (SRs) and meta-analyses (MA) that met our inclusion criteria. The individual SRs did not consistently favor the use of wearables, but the MA syntheses each found significant effects, favoring wearable devices in measures, including mean steps per day and mean time spent completing moderate-to-vigorous physical activity. The MA on adherence to cardiac rehabilitation (CR) found greater adherence to CR with the use of a mobile app than with no app support. Summary: Within this review, there were SRs demonstrating no difference and reviews indicating a positive impact with the use of wearables for physical activity/adherence measures in individuals with cardiovascular conditions, with no studies demonstrating a negative impact. The six SR/MAs included had methodological flaws, which introduced potential biases. Additionally, the MAs included a small number of studies, which limits their generalizability. The protocol for this review was registered on PROSPERO, the international prospective register of systematic reviews (#CRD42021286699).

Genetic Localization and Homologous Genes Mining for Barley Grain Size.

Grain size is an important agronomic trait determining barley yield and quality. An increasing number of QTLs (quantitative trait loci) for grain size have been reported due to the improvement in genome sequencing and mapping. Elucidating the molecular mechanisms underpinning barley grain size is vital for producing elite cultivars and accelerating breeding processes. In this review, we summarize the achievements in the molecular mapping of barley grain size over the past two decades, highlighting the results of QTL linkage analysis and genome-wide association studies. We discuss the QTL hotspots and predict candidate genes in detail. Moreover, reported homologs that determine the seed size clustered into several signaling pathways in model plants are also listed, providing the theoretical basis for mining genetic resources and regulatory networks of barley grain size.

FAP-α+ immunofibroblasts in oral lichen planus promote CD4+ T-cell infiltration via CCL5 secretion.

Oral lichen planus (OLP) is a T cell-mediated, chronic inflammatory disease. CD4+ T-cell infiltration plays a crucial role in the pathogenesis of OLP. Fibroblasts are activated under pathological conditions and perform various functions. This study was designed to explore the immune activation and biological functions of OLP fibroblasts on CD4+ T cells. We detected the expression of fibroblast activation protein-alpha (FAP-α) in the oral tissues of patients with OLP and healthy controls using immunohistochemistry. Furthermore, expression of FAP-α and C-C motif chemokine ligand 5 (CCL5) in fibroblasts isolated from oral tissues of patients with OLP and healthy controls was assayed by quantitative PCR, Western blotting and enzyme-linked immunosorbent assay. Moreover, we assessed the effects of fibroblasts on CD4+ T-cell proliferation, apoptosis and migration using flow cytometry and Transwell assays. We found that FAP-α expression in the oral tissues of patients with OLP was significantly higher than that in healthy controls. FAP-α and CCL5 expression levels were significantly upregulated in OLP fibroblasts. Moreover, OLP fibroblasts promoted CD4+ T-cell proliferation and migration and inhibited CD4+ T cell apoptosis. In summary, our findings indicate that OLP fibroblasts are immunologically activated and induce CD4+ T-cell infiltration in OLP.

DAB2IP down-regulates HSP90AA1 to inhibit the malignant biological behaviors of colorectal cancer.

BACKGROUND: Studies have shown that DAB2IP inhibits cancer progression, while HSP90AA1 promotes cancer progression. However, the specific regulatory mechanism of DAB2IP and HSP90AA1 in colorectal cancer (CRC) is not clear. Our aim is to investigate the role and mechanism of DAB2IP and HSP90AA1 in the development of CRC. METHODS: We used bioinformation to analyze the interaction between DAB2IP and HSP90AA1 and predict their downstream pathways. Then, a series of in vitro and in vivo experiments were conducted to reveal the role of DAB2IP and HSP90AA1 in the invasion and metastasis of colorectal cancer, and flow cytometry was used to explore their effects on apoptosis. RESULTS: Loss of DAB2IP was associated with poor prognosis of CRC. In contrast, elevated expression of HSP90AA1 was associated with the malignant behavior of CRC. The present study demonstrated a negative correlation between DAB2IP and HSP90AA1. Using bioinformatic analysis, we scanned SRP9 which was highly expressed in CRC, as a co-related gene of DAB2IP and HSP90AA1. Mechanistically, DAB2IP promoted apoptosis through HSP90AA1/SRP9/ASK1/JNK signaling axis in CRC. CONCLUSIONS: These findings provide evidence that DAB2IP-based therapy may enhance the anticancer effect of HSP90AA1 inhibitors, and combined targeting of DAB2IP and HSP90AA1 may be a powerful treatment strategy to combat CRC.

Spinal microglia-derived TNF promotes the astrocytic JNK/CXCL1 pathway activation in a mouse model of burn pain.

Burn injury-induced pain (BIP) is an extremely complicated condition usually resistant to analgesic drugs, while its pathogenesis remains unknown. Considerable attention has been attracted to elucidate the glial mechanisms in chronic pain. In this study, we initiatively used a mouse model of second-degree BIP to investigate the underlying non-neuronal mechanisms at the spinal cord level. Our behavioral results showed that hind-paw burn injury caused persistent allodynia and hyperalgesia for 2 weeks in mice. Further studies revealed that both microglia and astrocytes activated in a spatially- and temporally-dependent manner in spinal cord after burn injury. In addition, the phosphorylated p38 mitogen-activated protein kinase (MAPK)-mediated tumor necrosis factor (TNF) release in spinal microglia is essentially attributed to the early stage of BIP, while the c-Jun N-terminal kinase (JNK) MAPK-dependent chemokine CXCL1 expression is mainly involved in the maintenance of pain hypersensitivity. Most strikingly, burn injury-induced pain symptoms and the activation of astrocytes were significantly suppressed by TNF inhibitor Thalidomide. On the contrary, intrathecal injection of TNF caused apparent pain hypersensitivity, accompanied by the activation of astrocytes and the upregulation of CXCL1 via the JNK MAPK signaling pathway, indicating that TNF is the key cytokine in the interaction between microglia and astrocytes at the spinal level. Moreover, treatment with the CXCR2 receptor antagonist SB225002 to block the biological activities of CXCL1 significantly attenuated the mechanical allodynia and thermal hyperalgesia in this BIP model. Taken together, this study indicates that intervention of glial pathways provides a new perspective in the management of BIP.

Brain injury in preterm infants with surgical necrotizing enterocolitis: clinical and bowel pathological correlates.

BACKGROUND: The objective of this study was to determine the risk factors and outcomes of white matter brain injury (WMBI) on magnetic resonance imaging (MRI) at term-equivalent age in infants with surgical necrotizing enterocolitis (NEC). METHODS: This retrospective study compared clinical/pathological information between infants with and those without WMBI. RESULTS: Out of 69 infants with surgical NEC, 17 (24.6%) had mild WMBI, 13 (18.8%) had moderate WMBI, and six (8.7%) had severe WMBI on the brain MRI. Several clinical factors (gestational age, more red blood cell (RBC) transfusions before NEC onset, pneumoperitoneum, earlier NEC onset age, postoperative ileus, acute kidney injury (AKI) by serum creatinine, postnatal steroids, hospital stay) and histopathological findings (necrosis, hemorrhage) had univariate associations with WMBI. Associations with RBC transfusion (odds ratio (OR) 23.6 [95% confidence interval (CI): 4.73-117.97]; p = 0.0001), age at NEC onset (OR 0.30 [95%CI: 0.11-0.84]; p = 0.021), necrosis (OR 0.10 [95%CI: 0.01-0.90]; p = 0.040), and bowel hemorrhage (OR 7.79 [95%CI: 2.19-27.72]; p = 0.002) persisted in multivariable association with grade 3-4 WMBI. The infants with WMBI had lower mean motor, cognitive, language scores, and higher ophthalmic morbidity at 2 years of age. CONCLUSIONS: The WMBI was most likely associated with earlier NEC onset, higher RBC transfusions, and less necrosis and greater hemorrhage lesions on intestinal pathology in preterm infants with surgical NEC. IMPACT: In preterm infants with surgical NEC, brain MRI showed injury in the white matter in 52%, gray matter in 10%, and cerebellar region in 30%. Preterm infants with severe WMBI (grade 3-4) had less necrosis and greater hemorrhagic lesions on histopathology of the bowel. Preterm infants with WMBI were more likely to have a more severe postoperative course, AKI, and longer length of hospitalization. Neuroprotective strategies to prevent brain injury in preterm infants with surgical NEC are needed with the goal of improving the neurodevelopmental outcomes.

Long-term administration of sirolimus does not affect the physical development of children with tuberous sclerosis complex.

PURPOSE: There was no evidence whether the mammalian/mechanistic target of rapamycin pathway hyperactivation and long-term use of mTOR inhibitors have any effects on the physical development of children. The aim was to evaluate these effects by comparing the physical development of children with TSC and normal children. METHODS: A total of 120 eligible children were enrolled. They were administered sirolimus and followed for at least 12 months. Height, weight, BMI and lipid metabolism index were collected during treatment. Pearson's chi-square and Fisher's exact test were used for comparison of proportions of patients exhibiting normal and abnormal physical growth before and after 1 year of treatment. Logistic regression was used to evaluate the influence of age, sex and abnormal lipid metabolism on the increased BMIs of TSC patients after treatment. RESULTS: Most of the enrolled TSC children were in the normal height, weight and BMI ranges at baseline (91.7%, 95.8% and 78.3%, respectively). Most remained in the normal height, weight and BMI ranges after 1 year of sirolimus treatment (94.2%, 95% and 76.7%, respectively). There was no significant difference in the proportion of physical development before and after treatment (p > 0.05). Thirty-eight (38/106, 35.8%) patients had increased BMIs after 1 year of treatment, but there was no significant correlation between age, sex and lipid metabolism and increased BMI. CONCLUSIONS: Overactivation of the mTOR pathway and long-term administration of sirolimus does not affect the physical development of children with TSC.

Clinical Correlates of Moderate-to-Severe Bronchopulmonary Dysplasia in Preterm Infants following Surgical Necrotizing Enterocolitis.

OBJECTIVE: The aim of the study is to determine clinical correlates of moderate to severe bronchopulmonary dysplasia (BPD) in preterm infants following surgical necrotizing enterocolitis (NEC). STUDY DESIGN: This is a retrospective, single-center cohort study comparing patients with moderate to severe BPD to patients with non/mild BPD among surgical NEC infants. BPD was defined by NIH 2001 consensus definition. RESULTS: Of 92 consecutive neonates with surgical NEC, 77% (71/92) had moderate/severe BPD and 22% (21/92) had non/mild BPD. The patent ductus arteriosus (PDA) was significantly higher in those developing moderate/severe BPD (67.6% [48/71]) than non/mild BPD (28.6% [6/21]; p = 0.001). Postoperatively, infants with moderate/severe BPD had more severe acute kidney injury (AKI; 67.6 [48/71] vs. 28.6% [6/21]; p = 0.001), were intubated longer (40.5 [interquartile (IQR): 12, 59] vs. 6 days [IQR: 2, 13]; p <0.001), received more parenteral nutrition (109 [IQR: 77, 147] vs. 55 days [IQR: 19, 70]; p <0.001), developed higher surgical morbidity (46.5 [33/71] vs. 14.3% [3/21]; p = 0.008), had more intestinal failure (62.5 vs. 13.3%; p <0.001), required a longer hospital stay (161 [IQR: 112, 186] vs. 64 days [IQR: 20, 91]; p <0.001), and were more likely to need home oxygen. In a multivariable analysis, lower birth weight (OR = 0.3, [95% confidence interval (CI): 0.1-0.5]; p = 0.001), PDA (OR = 10.3, [95% CI: 1.6-65.4]; p = 0.014), and longer parenteral nutritional days (OR = 8.8; [95% CI: 2.0-43.0]; p = 0.005) were significantly and independently associated with higher odds of moderate/severe versus non-/mild BPD. CONCLUSION: Development of moderate/severe BPD occurred in the majority of preterm infants with surgical NEC in this consecutive series. Preterm infants with moderate/severe BPD were more likely to have a PDA before NEC. Development of moderate/severe BPD was associated with significantly greater burden and duration of postoperative morbidity following surgical NEC. Identifying surgical NEC infants at increased risk of moderate/severe BPD and developing lung protection strategies may improve surgical NEC outcomes. KEY POINTS: · Three-fourths of preterm infants experienced severe lung injury following surgical NEC.. · The infants with severe moderate/severe BPD were most likely associated with greater duration of postoperative morbidity.. · There is need to understand and develop lung protective strategies in infants with surgical NEC..

Versatile Dicyanomethylene-Based Fluorescent Probes for the Detection of ß-Amyloid in Alzheimer's Disease: A Theoretical Perspective.

Motivated by the growing demand for target chemosensors designed with diagnostic or therapeutic capability for fibrils related to amyloidosis diseases, we investigated in the present work the response mechanism of dicyanomethylene-based fluorescent probes for amyloid fibril using a combined approach, including molecular docking, quantum mechanics/molecular mechanics (QM/MM), and the quantum chemical method. Various binding modes for the probes in ß-amyloid (Aß) are discussed, and the fibril environment-induced molecular optical changes at the most stable site are compared to the fibril-free situation in aqueous environments. The results reveal that the fluorescence enhancement for the probes in Aß observed experimentally is an average consequence over multiple binding sites. In particular, the conformational difference, including conjugation length and donor effect, significantly contributes to the optical property of the studied probes both in water and fibril. To further estimate the transition nature of the molecular photoabsorption and photoemission processes, the hole-electron distribution and the structural variation on the first excited state of the probes are investigated in detail. On the basis of the calculations, structure-property relationships for the studied chemosensors are established. Our computational approach with the ability to elucidate the available experimental results can be used for designing novel molecular probes with applications to Aß imaging and the early diagnosis of Alzheimer's disease.

DOC-2/DAB2 interactive protein destabilizes c-Myc to impair the growth and self-renewal of colon tumor-repopulating cells.

Colorectal carcinoma (CRC) remains a huge challenge in clinical treatment due to tumor metastasis and recurrence. Stem cell-like colon tumor-repopulating cells (TRCs) are a subpopulation of cancer cells with highly tumorigenic and chemotherapy resistant properties. The core transcription factor c-Myc is essential for maintaining cancer stem-like cell phenotypes, yet its roles and regulatory mechanisms remain unclear in colon TRCs. We report that elevated c-Myc protein supported formation and growth of TRC spheroids. The tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) suppressed c-Myc expression to inhibit TRC expansion and self-renewal. Particularly, DAB2IP disrupted c-Myc stability through glycogen synthase kinase 3ß/protein phosphatase 2A-B56α-mediated phosphorylation and dephosphorylation cascade on c-Myc protein, leading to its eventual degradation through the ubiquitin-proteasome pathway. The expression of DAB2IP was negatively correlated with c-Myc in CRC specimens. Overall, our results improved mechanistic insight into how DAB2IP suppressed TRC growth and self-renewal.