DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

A plant immune protein enables broad antitumor response by rescuing microRNA deficiency.

Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small-RNA-mediated immune response in plants but is absent in vertebrates. Here, we show that ectopic expression of plant RDR1 can generally inhibit cancer cell proliferation. In many human primary tumors, abnormal microRNA isoforms with 1-nt-shorter 3' ends are widely accumulated. RDR1 with nucleotidyltransferase activity can recognize and modify the problematic AGO2-free microRNA duplexes with mononucleotides to restore their 2 nt overhang structure, which eventually rescues AGO2-loading efficiency and elevates global miRNA expression to inhibit cancer cell-cycle specifically. The broad antitumor effects of RDR1, which can be delivered by an adeno-associated virus, are visualized in multiple xenograft tumor models in vivo. Altogether, we reveal the widespread accumulation of aberrant microRNA isoforms in tumors and develop a plant RDR1-mediated antitumor stratagem by editing and repairing defective microRNAs.

Calcium-sensing receptor and NF-κB pathways in TN breast cancer contribute to cancer-induced cardiomyocyte damage via activating neutrophil extracellular traps formation.

Cardiovascular disorders are commonly prevalent in cancer patients, yet the mechanistic link between them remains poorly understood. Because neutrophil extracellular traps (NETs) have implications not just in cardiovascular diseases (CVD), but also in breast cancer (BC), it was hypothesized to contribute to CVD in the context of oncogenesis. We established a mouse model using nude mice to simulate liver metastasis of triple-negative BC (TNBC) through the injection of MDA-MB-231 cells. Multiple imaging and analysis techniques were employed to assess the cardiac function and structure, including echocardiography, HE staining, Masson staining, and transmission electron microscopy (TEM). MDA-MB-231 cells underwent treatment with a CaSR inhibitor, CaSR agonist, and NF-κB channel blocker. The phosphorylation of NF-κB channel protein p65 and the expression and secretion of IL-8 were assessed using qRT-PCR, Western Blot, and ELISA, respectively. In addition, MDA-MB-231 cells were co-cultured with polymorphonuclear neutrophils (PMN) under varying conditions. The co-localization of PMN extracellular myeloperoxidase (MPO) and DNA were observed by cellular immunofluorescence staining to identify the formation of NETs. Then, the cardiomyocytes were co-cultured with the above medium that contains NETs or not, respectively; the effects of NETs on cardiomyocytes apoptosis were perceived by flow cytometry. The ultrastructural changes of myocardial cells were perceived by TEM, and ELISA detected the levels of myocardial enzyme (LDH, MDA and SOD). Overall, according to our research, CaSR has been found to have a regulatory role in IL-8 secretion in MDA-MB-231 cells, as well as in the formation of NETs by PMN cells. These findings suggest CaSR-mediated stimulation in PMN can lead to increased NETs formation and subsequently to cytotoxicity in cardiomyocytes, which potentially via activation of the NF-κB signaling cascade of BC cell.

IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Peripheral blood circular RNA circ-0008102 may serve as a novel clinical biomarker in beta-thalassemia patients.

Circular RNA circ-0008102 has previously been found dysregulated in ß-thalassemia (ß-thal) in circRNAs microarray (GSE196682 and GSE241141). Our study is aimed at identifying whether circ-0008102 could be a novel biomarker in ß-thal. The peripheral blood of pediatric ß-thal patients with (n = 39) or without (n = 20) blood transfusion and healthy controls (n = 30) was selected. qRT-PCR, ROC curve analysis, Spearman correlation analysis, and FISH were used to analyze clinical value of circ-0008102. qRT-PCR confirmed that circ-0008102 expression in pediatric ß-thal patients without blood transfusion was significantly higher. ROC curves analysis showed that the AUC of circ-0008102 for differentiating patients without blood transfusion from patients with blood transfusion and healthy controls with an AUC of 0.733 and 0.711. Furthermore, circ-0008102 expression was positively correlated with the levels of RBC, HbF, ß-globin, and γ-globin mRNA, but was negatively corrected with the levels of HbA and Cr. circ-0008102 was mainly located in the cytoplasm. circ-0008102 could induce the activation of γ-globin and negatively regulate the expression of the five highest-ranking candidate miRNAs (miR-372-3p, miR-329-5p, miR-198, miR-152-5p, and miR-627-3p) in K562 cells. CONCLUSION: We demonstrate that peripheral blood upregulated circ-0008102 may serve as a novel clinical biomarker for pediatric ß-thal without blood transfusion. WHAT IS KNOWN: • CircRNAs are known to be involved in various human diseases, and several circRNAs are regarded as a class of promising blood-based biomarkers for detection of ß-thal. • CircRNAs exert biological functions by epigenetic modification and gene expression regulation, and dysregulated circRNAs in ß-thal might be involved in the induction of HbF in ß-thal. WHAT IS NEW: • Peripheral blood circ-0008102 maybe serve as a novel clinical biomarker for detection of pediatric ß-thal without blood transfusion. • Circ-0008102 participates in the pathogenesis of ß-thal through regulating γ-globin expression, and negatively regulates the expression of miR-372-3p, miR-329-5p, miR-198, miR-152-5p and miR-627-3p.

First Report of Filipino ß0-Thalassemia/ß-Thalassemia in a Chinese Family.

A pregnant woman living in Fujian Province, southeastern China, presented due to a risk of having a baby with ß-thalassemia major, during her second pregnancy, since she and her husband were suspected as ß-thalassemia carriers and their affected daughter was a transfusion-dependent patient. Using the common α-thalassemia and ß-thalassemia genotypes test, the pregnant woman was diagnosed as a ß-thalassemia carrier with ßIVS-2 - 654 (C→T)/ßN genotype and her daughter had a homozygosity for IVS - 2 - 654 (C→T) mutation, however, no abnormalities were detected in her husband. SMRT identified a Filipino ß0-deletion in her husband, and MLPA also revealed an unknown deletion in the HBB gene. Electrophoresis showed approximately 350 bp of the PCR product, and the ß-Filipino genotype presented novel fracture fragments ranging from 5,112,884 to 5,231,358 bp, and lacked a 118,475 bp fragment relative to the wild-type sequence. The daughter was therefore diagnosed with the ßIVS-2 - 654 (C→T)/ßFilipino genotype. Prenatal diagnosis with umbilical cord blood at 27th week of gestation showed heteroztgosity for IVS - 2 - 654 (C→T) mutation in the fetus and continued pregnancy was recommended. In conclusion, we identified the Filipino ß0-deletion in a Chinese family, from Fujian area, for the first time, during prenatal screening.

Macromolecules Promoting Robust Zinc Anode by Synergistic Coordination Effect and Charge Redistribution.

Zn dendrite formation is the main obstacle to commercializing aqueous zinc-ion batteries (ZIBs). α-cyclodextrin (α-CD) is proposed as an environmentally friendly macromolecule additive in the ZnSO4 -based electrolyte to obtain stable and reversible Zn anodes. The results show that α-CD molecules' unique 3D structure can effectively regulate the mass transfer of the electrolyte components and isolate the Zn anode from H2 O molecules. The α-CD provides abundant electrons to the Zn (002) crystallographic plane, which induces charge density redistribution. Such an effect relieves the reduction and aggregation of Zn2+ cations while protecting the Zn metal anode from water molecules. Finally, a small amount of α-CD additive (0.01 M) can enhance the performance of Zn significantly in Zn||Cu cells (1980 cycles with 99.45% average CE) and Zn||Zn cells (8000 h ultra-long cycle life). The excellent practical applicability was further verified in Zn||MnO2 cells.

P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination.

BACKGROUND: Intrauterine adhesion (IUA) is a recurrent and refractory reproductive dysfunction disorder for which menstrual blood-derived stromal cells (MenSCs) might be a promising intervention. We reported that administration of MenSCs-derived exosomes (MenSCs-EXO) could achieve similar therapeutic effects to MenSCs transplantation, including alleviating endometrial fibrosis and improving fertility in IUA rats. The mass spectrometry sequencing result suggested that UBR4, a member of the proteasome family, was abundantly enriched in MenSCs-EXO. This study aimed to investigate the key role of UBR4 in MenSCs-EXO for the treatment of IUA and the specific molecular mechanism. RESULTS: UBR4 was lowly expressed in the endometrial stromal cells (EndoSCs) of IUA patients. MenSCs-EXO treatment could restore the morphology of IUA endometrium, reduce the extent of fibrosis, and promote endometrial and vascular proliferation. Knockdown of UBR4 in MenSCs did not affect the characteristics of exosomes but attenuated the therapeutic effect of exosomes. UBR4 in MenSCs-EXO could alleviate endometrial fibrosis by boosting YAP ubiquitination degradation and promoting YAP nuclear-cytoplasmic translocation. Moreover, P65 could bind to the UBR4 promoter region to transcriptionally promote the expression level of UBR4 in MenSCs. CONCLUSION: Our study clarified that MenSCs-EXO ameliorated endometrial fibrosis in IUA primarily by affecting YAP activity mediated through UBR4, while inflammatory signaling P65 may affect UBR4 expression in MenSCs to enhance MenSCs-EXO therapeutic effects. This revealed a novel mechanism for the treatment of IUA with MenSCs-EXO, proposing a potential option for the clinical treatment of endometrial injury.

Effects of soil amendments on soil acidity and crop yields in acidic soils: A world-wide meta-analysis.

Soil amendments, including lime, biochar, industrial by-products, manure, and straw are used to alleviate soil acidification and improve crop productivity. Quantitative insight in the effect of these amendments on soil pH is limited, hampering their appropriate use. Until now, there is no comprehensive evaluation of the effects of soil amendments on soil acidity and yield, accounting for differences in soil properties. We synthesized 832 observations from 142 papers to explore the impact of these amendments on crop yield, soil pH and soil properties, focusing on acidic soils with a pH value below 6.5. Application of lime, biochar, by-products, manure, straw and combinations of them significantly increased soil pH by 15%, 12%, 15%, 13%, 5% and 17%, and increased crop yield by 29%, 57%, 50%, 55%, 9%, and 52%, respectively. The increase of soil pH was positively correlated with the increase in crop yield, but the relationship varied among crop types. The most substantial increases in soil pH and yield in response to soil amendments were found under long-term applications (>6 year) in strongly acidic (pH < 5.0) sandy soils with a low cation exchange capacity (CEC, <100 mmolc kg-1) and low soil organic matter content (SOM, <12 g kg-1). Most amendments increased soil CEC, SOM and base saturation (BS) and decreased soil bulk density (BD), but lime application increased soil BD (1%) induced by soil compaction. Soil pH and yield were positively correlated with CEC, SOM and BS, while yield declined when soils became compacted. Considering the impact of the amendments on soil pH, soil properties and crop yield as well as their costs, the addition of lime, manure and straw seem most appropriate in acidic soils with an initial pH range from <5.0, 5.0-6.0 and 6.0-6.5, respectively.

Fertilization as the most critical factor affecting yield response and agronomic efficiency of phosphorus in Chinese rice production: evidence from multi-location field trials.

BACKGROUND: Efficient utilization of phosphorus (P) has been a major challenge for sustainable agriculture. However, the responses of fertilizer rate, region, soil properties, cropping systems and genotypes to P have not been investigated comprehensively and systematically. RESULTS: A comprehensive analysis of 9863 fertilizer-P experiments on rice cultivation in China showed that rice yield  increased first and then fell down with the addition of P fertilizer, and the highest yield of 7963 kg ha-1 was observed under 100% P treatment. Under 100% P treatment, the yield response of applied P (YRP ) and agronomic efficiency of applied P (AEP ) were 12.8% and 30.1 kg ha-1 , respectively. Lower soil pH (< 5.5) and organic matter (< 30.0 g kg-1 ) were associated with lower YRP and AEP . By contrast, soil available P < 25.0 mg kg-1 resulted in decreased YRP (15.3 to 11.4%) and AEP (32.3 kg kg-1 to 26.2 kg kg-1 ), whereas soil available P > 25.0 mg kg-1 maintained the relatively stable YRP and AEP . Also, the YRP and AEP were significantly higher for single-cropping rice compared to other cropping systems. Moreover, the rice genotypes such as 'Longdun', 'Kendao' and 'Jigeng' had higher YRP and AEP than the average value. Overall, the fertilizer-P rate was the primary factor affecting YRP and AEP , and the recommended P fertilizer rate can be reduced by 9-21 kg P ha-1 compared to existing expert recommendations. CONCLUSION: The present study highlights the role of fertilizer-P rate in maximizing the YRP and AEP , thereby providing a strong basis for future fertilizer management in rice cultivation systems. © 2023 Society of Chemical Industry.

Treatment of Primary Pigmented Nodular Adrenocortical Disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.

Correlation between depression and intimacy in lung cancer patients and their family caregivers.

BACKGROUND: Cancer impacts both patients and their family caregivers. This study aimed to explore the interdependence between depression and intimacy in lung cancer patients and their family caregivers, providing the basis for developing a patient-caregiver centered dyadic intervention. METHODS: This cross-sectional study recruited 182 dyads of lung cancer patients and their family caregivers using a convenient sampling. The depression subscale of the Hospital Anxiety and Depression Scale (HADS) and the Mutuality Scale (MS) were used to measure participants' depression and intimacy respectively; and the correlation between depression and intimacy in patients and caregivers was analyzed by establishing the actor-partner interdependence model. RESULTS: Thirty four percent of the patients and 19.2% of the caregivers were at risk of depression, with an intimacy score of 2.67 ± 0.74 points and 2.6 ± 0.86 points, respectively; Pearson correlation analysis showed that there was a positive correlation between the depression score (r = 0.226, P < 0.01) and intimacy score (r = 0.344, P < 0.01) in patients and caregivers; and the results of actor-partner interdependence model showed that caregivers' depression had an actor effect on their own intimacy (b = -0.054, P = 0.004) as well as a partner effect on patients' intimacy (b = -0.041, P = 0.011). However, patients' depression has no influence on the intimacy of patients or caregivers. CONCLUSIONS: There is an interdependent relationship between depression and intimacy in lung cancer patients and family caregivers. Therefore, dyadic interventions can help them to cope with cancer together.

Enhancing Comprehensive Analysis of Newly Synthesized Proteins Based on Cleavable Bioorthogonal Tagging.

Protein synthesis and degradation responding to environmental cues is critical for understanding the mechanisms involved. Chemical proteomics introducing bioorthogonal tagging into proteins and isolation by biotin affinity purification is applicable for enrichment of newly synthesized proteins (NSPs). Current enrichment methods based on biotin-streptavidin interaction lack efficiency to release enriched NSPs under mild conditions. Here we designed a novel method for enriching newly synthesized peptides by click chemistry followed by release of enriched peptides via tryptic digestion based on cleavable bioorthogonal tagging (CBOT). CBOT-modified peptides can further enhance identification in mass spectrometry analysis and provide a confirmation by small mass shift. Our method achieved an improvement in specificity (97.1%) and sensitivity for NSPs in cell lysate, corresponding to profiling at a depth of 4335 NSPs from 2 mg of starting materials in a single LC-MS/MS run. In addition, the CBOT strategy can quantify NSPs when coupling a pair of isotope-labeled azidohomoalanine (AHA/hAHA) with decent reproducibility. Furthermore, we applied it to analyze newly synthesized proteomes in the autophagy process after 6 h rapamycin stimulation in cells, 2910 NSPs were quantified, and 337 NSPs among them were significantly up- and down-regulated. We envision CBOT as an effective and alternative approach for bioorthogonal chemical proteomics to study stimuli-sensitive subsets.

miR-30b-5p inhibits proliferation, invasion, and migration of papillary thyroid cancer by targeting GALNT7 via the EGFR/PI3K/AKT pathway.

BACKGROUND: Papillary thyroid carcinoma (PTC) is a common endocrine tumor. Increasing evidence has shown that microRNA dysfunction is involved in the occurrence and development of cancer. The expression of MicroRNA-30b-5p (miR-30b-5p) was down-regulated in PTC; however, its role in the development of PTC is not clear. Hence, this study aimed to explore the role and mechanism of miR-30b-5p in the occurrence and development of PTC. METHODS: The qRT-PCR assay was used to detect the expression of miR-30b-5p in 60 cases of papillary thyroid carcinoma along with their matched non-cancerous tissues. This study explored the biological function of miR-30b-5p by the functional gain and loss experiments in vitro and vivo. The direct target gene of miR-30b-5p and its signaling pathway was identified through bioinformatics analysis, qRT-PCR, western blot, rescue experiments, and double luciferase 3'-UTR report analysis. RESULTS: This study demonstrated that the low expression of miR-30b-5p is related to poor clinicopathological features. Functionally, the overexpression of miR-30b-5p inhibited the proliferation, invasion, and migration of PTC cells. Bioinformatics and luciferase analysis showed that GALNT7 is the direct and functional target of miR-30b-5p. Moreover, miR-30b-5p inhibited the proliferation of PTC in vivo by inhibiting the expression of GALNT7. The studies on the mechanism have shown that GALNT7 promotes cell proliferation and invasion by activating EGFR/PI3K/AKT kinase pathway, which can be attenuated by the kinase inhibitors. CONCLUSIONS: Overall, miR-30b-5p inhibited the progression of papillary thyroid carcinoma by targeting GALNT7 and inhibiting the EGFR/PI3K/AKT pathway.

Brucellosis screening and follow-up of seropositive asymptomatic subjects among household members of shepherds in China.

To measure the seroprevalence of high-exposure populations in brucellosis endemic areas and report the outcome and duration of seropositive asymptomatic subjects, we screened 595 family members of shepherds in Jilin Province, China and then followed up 15 seropositive asymptomatic subjects for 18 months. We found that the seropositive rate of 15.5%. Nearly half of seropositive asymptomatic subjects (7/15) developed into brucellosis in the short term; others were still seropositive asymptomatic or had decreased SAT titer in a longer time.

Effect of long-term growth hormone replacement on glucose metabolism in adults with growth hormone deficiency: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis was performed to summarize the long-term (more than 6 months) effect of growth hormone (GH) replacement therapy (GHRT) on glucose metabolism among adults growth hormone deficiency (AGHD) patients. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library databases from inception till March 2020 for relevant studies evaluating the effect of GHRT on glucose metabolism in AGHD patients. Results were stratified into two periods (6-12 months and more than12 months) according to the length of follow-up. RESULTS: Thirty-three studies including 11 randomized controlled trials (RCTs) and 22 prospective open-label studies (POLs) were included in the meta-analysis. The findings of this meta-analysis showed that GH supplementation with a duration of 6-12 months among adults with growth hormone deficiency (GHD) significantly increased fasting plasma glucose (FPG) (SMD 0.37; 95% CI 0.25 to 0.49; I2 = 0%; P < 0.00001), fasting insulin (FI) (SMD 0.2; 95% CI 0.08 to 0.33; I2 = 9%; P = 0.001), glycated hemoglobin (HbA1c) (SMD 0.31; 95% CI 0.17 to 0.46; I2 = 10%; P < 0.0001) and homeostasis model of assessment-insulin resistance (HOMA-IR) (SMD 0.28; 95% CI 0.08 to 0.47; I2 = 13%; P = 0.006). Notably, GH intervention with a duration of more than 12 months showed no significant effect on FI (SMD 0.14; 95% CI - 0.09 to 0.37; I2 = 0%; P = 0.24), HbA1c (SMD - 0.02; 95% CI - 0.3 to 0.26; I2 = 72%; P = 0.89) and HOMA-IR levels (SMD 0.04; 95% CI - 0.24 to 0.31; I2 = 0%; P = 0.80) in adults with GHD. However, FPG levels in AGHD were still significantly increased with more than one year intervention period (SMD 0.41; 95% CI 0.29 to 0.53; I2 = 0%; P < 0.00001). CONCLUSION: Overall, the current meta-analysis demonstrated that GHRT with a shorter duration (6-12 months) led to a deterioration in glucose metabolism including FPG, FI, HbA1c and HOMA-IR in AGHD patients. However, the negative effects of GH therapy on these glucose homeostasis parameters were not seen in longer duration of GHRT, except for FPG.

The consequences of cavity creation on the folding landscape of a repeat protein depend upon context.

The effect of introducing internal cavities on protein native structure and global stability has been well documented, but the consequences of these packing defects on folding free-energy landscapes have received less attention. We investigated the effects of cavity creation on the folding landscape of the leucine-rich repeat protein pp32 by high-pressure (HP) and urea-dependent NMR and high-pressure small-angle X-ray scattering (HPSAXS). Despite a modest global energetic perturbation, cavity creation in the N-terminal capping motif (N-cap) resulted in very strong deviation from two-state unfolding behavior. In contrast, introduction of a cavity in the most stable, C-terminal half of pp32 led to highly concerted unfolding, presumably because the decrease in stability by the mutations attenuated the N- to C-terminal stability gradient present in WT pp32. Interestingly, enlarging the central cavity of the protein led to the population under pressure of a distinct intermediate in which the N-cap and repeats 1-4 were nearly completely unfolded, while the fifth repeat and the C-terminal capping motif remained fully folded. Thus, despite modest effects on global stability, introducing internal cavities can have starkly distinct repercussions on the conformational landscape of a protein, depending on their structural and energetic context.

Tunable dielectric polarization and breakdown behavior for high energy storage capability in P(VDF-TrFE-CFE)/PVDF polymer blended composite films.

Polymer dielectrics with high dielectric performances and superior discharge energy capability are highly desirable for advanced electrostatic capacitor applications. However, the paradoxical relationship between dielectric polarization and electric breakdown behavior generally hinder their further enhancement in energy storage performances. Herein, polymer blended composite films with high energy storage capability were successfully fabricated by blending together poly(vinylidene fluoride) (PVDF) polymer and poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) (P(VDF-TrFE-CFE)) terpolymer. The P(VDF-TrFE-CFE) terpolymer has a high dielectric constant to provide a large electric displacement under an applied electric field far below its breakdown field, which is anticipated to modulate the dielectric polarization behavior of PVDF polymer when blended in different proportions. Consequently, the polymer blended composite film consisting of 20 wt% (P(VDF-TrFE-CFE)) terpolymer exhibits a high discharge energy density of 13.63 J cm-3 at an enhanced breakdown strength of 480 MV m-1. This obtained high discharge energy density is 84% higher than the pure PVDF film and 582% higher than a commercialized biaxially oriented polypropylene (BOPP). Large interfacial polarization and strong interaction of polymer chains between the PVDF polymer and P(VDF-TrFE-CFE) terpolymer may contribute to the tunable dielectric constant and electric breakdown strength, thus promoting the energy storage capability. This work establishes a facile, but effective approach to achieve the high energy storage capability of PVDF polymer-based flexible composite films for capacitive energy storage applications.

Absorption enhancement by a period array of nano-grooves in gold substrate.

Comprehensive investigations of absorption enhancement by a period array of nano-grooves in gold substrate are provided. A simple Fabry-Perot model is presented to explore impact factors on absorption enhancement. The impacts of structural parameters on absorption enhancement for an array of nano-grooves are explored and discussed. Our calculations show that complete absorption (about 1) can be obtained with the groove depth fulfilling the Fabry-Perot resonance condition. The effect of groove width on absorption for a trapezoidal groove array is slightly different from that for a rectangular groove array, because of the impact of single-pass loss in the grooves. Surface plasmon resonance that can carry most of the energy away from grooves and propagate along the metal surface could lead to extremely low absorption for a period array of nano-grooves. Our discussions identify two key roles in absorption enhancement for a nano-groove array: the fundamental groove mode resonance and the generation of surface plasma polaritons. In addition, the analysis of absorption enhancement for an array of trapezoidal grooves can also provide a comprehensive contribution of Fabry-Perot resonance and electromagnetic interaction along the bevel edges of the trapezoidal grooves.

Cardiovascular effects of growth hormone (GH) treatment on GH-deficient adults: a meta-analysis update.

BACKGROUND: It is still unclear whether growth hormone (GH) replacement is able to improve cardiovascular parameters in adults with GH deficiency (AGHD) from the updated clinical trials reported to date. METHODS AND RESULTS: We systematically reviewed clinical trials of GH treatment on AGHD patients in recent decade, and evaluated the effects of GH on cardiovascular parameters assessed by echocardiography. 11 clinical trials were identified in 3 bibliographic databases. We conducted a combined analysis of effects on four aspects: General indicators: baseline heart rate (BHR), peak heart rate (PHR), systolic blood pressure (SBP), diastolic blood pressure (DBP); Cardiac structure: left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular interventricular septum (LVIS), left ventricular mass (LVM), left ventricular posterior wall (LVPW); Cardiovascular function: deceleration time of E wave (DT), E/A ratio (E/A), ejection fraction (EF), NT-BNP; Life quality: peak VO2, VE/VCO2 slope. Overall effect size was used to evaluate significance, and weighted mean difference after GH treatment was given to appreciate size of the effect. GH treatment was associated with a significant increase in BHR (3.03[2.00, 4.06]), LVIS (0.50[0.43, 0.57]), LVPW (0.50[0.43, 0.57]), and EF (2.12[1.34, 2.90]). Overall effect sizes were negative significant for DBP (- 1.19[- 2.33, - 0.05]), LVEDV (- 9.84[- 16.53, - 3.15]), NT-BNP (- 206.34[- 308.95, - 103.72]), and VE/VCO2 slope (- 2.31[- 2.92, - 1.71]). CONCLUSIONS: As assessed by echocardiography, GH administration may improve the general vital signs and life quality of AGHD patients, based on the positive effect on BHR and negative effects on DBP and VE/VCO2 slope. Also, GH treatment would influence the structure of heart with positive effects on LVIS, LVPW and negative effect on LVEDV, which together with the increase of EF and decrease of NT-BNP, then resulting in improving the systolic function of AGHD patients.