Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates.

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary timescales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning shapes germline mutation signatures and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.

MicroRNA directly enhances mitochondrial translation during muscle differentiation.

MicroRNAs are well known to mediate translational repression and mRNA degradation in the cytoplasm. Various microRNAs have also been detected in membrane-compartmentalized organelles, but the functional significance has remained elusive. Here, we report that miR-1, a microRNA specifically induced during myogenesis, efficiently enters the mitochondria where it unexpectedly stimulates, rather than represses, the translation of specific mitochondrial genome-encoded transcripts. We show that this positive effect requires specific miR:mRNA base-pairing and Ago2, but not its functional partner GW182, which is excluded from the mitochondria. We provide evidence for the direct action of Ago2 in mitochondrial translation by crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq), functional rescue with mitochondria-targeted Ago2, and selective inhibition of the microRNA machinery in the cytoplasm. These findings unveil a positive function of microRNA in mitochondrial translation and suggest a highly coordinated myogenic program via miR-1-mediated translational stimulation in the mitochondria and repression in the cytoplasm.

Simple oligonucleotide-based multiplexing of single-cell chromatin accessibility.

Microdroplet single-cell ATAC-seq is widely used to measure chromatin accessibility, however, highly scalable and simple sample multiplexing procedures are not available. Here, we present a transposome-assisted single nucleus barcoding approach for ATAC-seq (SNuBar-ATAC) that utilizes a single oligonucleotide adaptor for multiplexing samples during the existing tagmentation step and does not require a pre-labeling procedure. The accuracy and scalability of SNuBar-ATAC was evaluated using cell line mixture experiments. We applied SNuBar-ATAC to investigate treatment-induced chromatin accessibility dynamics by multiplexing 28 mice with lung tumors that received different combinations of chemo, radiation, and targeted immunotherapy. We also applied SNuBar-ATAC to study spatial epigenetic heterogeneity by multiplexing 32 regions from a human breast tissue. Additionally, we show that SNuBar can multiplex single cell ATAC and RNA multiomic assays in cell lines and human breast tissue samples. Our data show that SNuBar is a highly accurate, easy-to-use, and scalable system for multiplexing scATAC-seq and scATAC and RNA co-assay experiments.

Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.

The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.

Pediatric Hepatoblastoma After Neoadjuvant Chemotherapy: Diagnostic Performance of MR in Staging POSTTEXT and Vascular Involvement.

BACKGROUND: The assessment of resectability after neoadjuvant chemotherapy of hepatoblastoma is dependent on Post-Treatment EXTENT of Disease (POSTTEXT) staging and its annotation factors P (portal venous involvement) and V (hepatic venous/inferior vena cava [IVC] involvement), but MR performance in assessing them remains unclear. PURPOSE: To assess the diagnostic performance of contrast-enhanced MR imaging for preoperative POSTTEXT staging and diagnosing vascular involvement in terms of annotation factors P and V in pediatric hepatoblastoma following neoadjuvant chemotherapy. STUDY TYPE: Retrospective. SUBJECTS: Thirty-five consecutive patients (17 males, median age, 24 months; age range, 6-98 months) with proven hepatoblastoma underwent preoperative MR imaging following neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 3.0 T; T2-weighted imaging (T2WI), T2WI with fat suppression, diffusion weighted imaging, radial stack-of-the-star/Cartesian 3D Dixon T1-weighted gradient echo imaging. ASSESSMENT: Three radiologists independently assessed the POSTTEXT stages and annotation factors P and V based on the 2017 PRE/POSTTEXT system. The sensitivities and specificities were calculated for 1) diagnosing each POSTTEXT stage; 2) discrimination of stages III and IV (advanced) from those stages I and II (non-advanced) hepatoblastomas; and 3) annotation factors P and V. The combination of pathologic findings and surgical records served as the reference standard. STATISTICAL TESTS: Sensitivity, specificity, Fleiss kappa test. RESULTS: The sensitivity and specificity ranges for discriminating advanced from non-advanced hepatoblastomas were 73.3%-80.0% and 80.0%-90.0%, respectively. For annotation factor P, they were 66.7%-100.0% and 90.6%, respectively. For factor V, they were 75.0% and 67.7%-83.9%, respectively. There was excellent, substantial, and moderate agreement on POSTTEXT staging (Fleiss kappa = 0.82), factors P (Fleiss kappa = 0.64), and factors V (Fleiss kappa = 0.60), respectively. DATA CONCLUSION: MR POSTTEXT provides reliable discrimination between advanced and non-advanced tumors, and MR has moderate to excellent specificity at identifying portal venous and hepatic venous/IVC involvement. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Inhaled nitric oxide and postoperative outcomes in cardiac surgery with cardiopulmonary bypass: A systematic review and meta-analysis.

Cardiac surgeries under cardiopulmonary bypass (CPB) are complex procedures with high incidence of complications, morbidity and mortality. The inhaled nitric oxide (iNO) has been frequently used as an important composite of perioperative management during cardiac surgery under CPB. We conducted a meta-analysis of published randomized clinical trials (RCTs) to assess the effects of iNO on reducing postoperative complications, including the duration of postoperative mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay, mortality, hemodynamic improvement (the composite right ventricular failure, low cardiac output syndrome, pulmonary arterial pressure, and vasoactive inotropic score) and myocardial injury biomarker (postoperative troponin I levels). Subgroup analyses were performed to assess the effect of modification and interaction. These included iNO dosage, the timing and duration of iNO therapy, different populations (children and adults), and comparators (other vasodilators and placebo or standard care). A comprehensive search for iNO and cardiac surgery was performed on online databases. Twenty-seven studies were included after removing the duplicates and irrelevant articles. The results suggested that iNO could reduce the duration of mechanical ventilation, but had no significance in the ICU stay, hospital stay, and mortality. This may be attributed to the small sample size of the most included studies and heterogeneity in timing, dosage and duration of iNO administration. Well-designed, large-scale, multicenter clinical trials are needed to further explore the effect of iNO in improving postoperative prognosis in cardiovascular surgical patients.

MCNN_MC: Computational Prediction of Mitochondrial Carriers and Investigation of Bongkrekic Acid Toxicity Using Protein Language Models and Convolutional Neural Networks.

Mitochondrial carriers (MCs) are essential proteins that transport metabolites across mitochondrial membranes and play a critical role in cellular metabolism. ADP/ATP (adenosine diphosphate/adenosine triphosphate) is one of the most important carriers as it contributes to cellular energy production and is susceptible to the powerful toxin bongkrekic acid. This toxin has claimed several lives; for example, a recent foodborne outbreak in Taipei, Taiwan, has caused four deaths and sickened 30 people. The issue of bongkrekic acid poisoning has been a long-standing problem in Indonesia, with reports as early as 1895 detailing numerous deaths from contaminated coconut fermented cakes. In bioinformatics, significant advances have been made in understanding biological processes through computational methods; however, no established computational method has been developed for identifying mitochondrial carriers. We propose a computational bioinformatics approach for predicting MCs from a broader class of secondary active transporters with a focus on the ADP/ATP carrier and its interaction with bongkrekic acid. The proposed model combines protein language models (PLMs) with multiwindow scanning convolutional neural networks (mCNNs). While PLM embeddings capture contextual information within proteins, mCNN scans multiple windows to identify potential binding sites and extract local features. Our results show 96.66% sensitivity, 95.76% specificity, 96.12% accuracy, 91.83% Matthews correlation coefficient (MCC), 94.63% F1-Score, and 98.55% area under the curve (AUC). The results demonstrate the effectiveness of the proposed approach in predicting MCs and elucidating their functions, particularly in the context of bongkrekic acid toxicity. This study presents a valuable approach for identifying novel mitochondrial complexes, characterizing their functional roles, and understanding mitochondrial toxicology mechanisms. Our findings, that utilize computational methods to improve our understanding of cellular processes and drug-target interactions, contribute to the development of therapeutic strategies for mitochondrial disorders, reducing the devastating effects of bongkrekic acid poisoning.

A 3-year follow-up study of outcomes associated with patterns of traditional acute and preventive migraine treatment: An administrative claims-based cohort study in the United States.

OBJECTIVE: To describe treatment patterns and direct healthcare costs over 3 years following initiation of standard of care acute and preventive migraine medications in patients with migraine in the United States. BACKGROUND: There are limited data on long-term (>1 year) migraine treatments patterns and associated outcomes. METHODS: This was a retrospective, observational cohort study using US claims data from the IBM® MarketScan® Research Database (January 2010-December 2017). Adults were included if they had a prescription claim for acute migraine treatments (AMT) or preventive migraine treatments (PMT) in the index period (January 2011-December 2014). The AMT cohort was categorized as persistent, cycled, or added-on subgroups; the PMT cohort was categorized PMT-persistent, switched without gaps, or cycled with gaps. Migraine-specific annual direct costs (2017 US$) across AMT and PMT cohort subgroups were summarized at baseline through 3 years from index (follow-up). RESULTS: During the index period, 20,778 and 42,259 patients initiated an AMT and a PMT, respectively. At the 3-year follow-up, migraine-specific direct costs were lower in the persistent subgroup relative to the non-persistent subgroups in both AMT (mean [SD]: $789 [$1741] vs. $2847 [$8149] in the added-on subgroup and $862 [$5426] for the cycled subgroup) and PMT cohorts (mean [SD]: $1817 [$5892] in the persistent subgroup vs. $4257 [$11,392] in the switched without gaps subgroup and $3269 [$18,540] in the cycled with gaps subgroup). Acute medication overuse was lower in the persistent subgroup (1025/6504 [27.2%]) vs. non-persistent subgroups (11,236/58,863 [32.2%] in cycled with gaps subgroup and 1431/6504 [39.4%] in the switched without gaps subgroup). Most patients used multiple acute (19,717/20,778 [94.9%]) or preventive (38,494/42,259 [91.1%]) pharmacological therapies over 3 years following treatment initiation. Gaps in preventive therapy were common; an average gap ranged from 85 to 211 days (~3-7 months). CONCLUSION: Migraine-specific annual healthcare costs and acute migraine medication overuse remained lowest among patients with persistent AMT and PMT versus non-persistent treatment. Study findings are limited to the US population. Future studies should compare costs and associated outcomes between newer preventive migraine medications in patients with migraine.

Unmasking Spatial Heterogeneity in Phytotoxicology Mechanisms Induced by Carbamazepine by Mass Spectrometry Imaging and Multiomics Analyses.

Previous studies have highlighted the toxicity of pharmaceuticals and personal care products (PPCPs) in plants, yet understanding their spatial distribution within plant tissues and specific toxic effects remains limited. This study investigates the spatial-specific toxic effects of carbamazepine (CBZ), a prevalent PPCP, in plants. Utilizing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), CBZ and its transformation products were observed predominantly at the leaf edges, with 2.3-fold higher concentrations than inner regions, which was confirmed by LC-MS. Transcriptomic and metabolic analyses revealed significant differences in gene expression and metabolite levels between the inner and outer leaf regions, emphasizing the spatial location's role in CBZ response. Notably, photosynthesis-related genes were markedly downregulated, and photosynthetic efficiency was reduced at leaf edges. Additionally, elevated oxidative stress at leaf edges was indicated by higher antioxidant enzyme activity, cell membrane impairment, and increased free fatty acids. Given the increased oxidative stress at the leaf margins, the study suggests using in situ Raman spectroscopy for early detection of CBZ-induced damage by monitoring reactive oxygen species levels. These findings provide crucial insights into the spatial toxicological mechanisms of CBZ in plants, forming a basis for future spatial toxicology research of PPCPs.

Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability.

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

Indolo[3,2-b]indole-based multi-resonance emitters for efficient narrowband pure-green organic light-emitting diodes.

Organic light-emitting diodes (OLEDs) utilizing multi-resonance (MR) emitters show great potential in ultrahigh-definition display benefitting from superior merits of MR emitters such as high color purity and photoluminescence quantum yields. However, the scarcity of narrowband pure-green MR emitters with novel backbones and facile synthesis has limited their further development. Herein, two novel pure-green MR emitters (IDIDBN and tBuIDIDBN) are demonstrated via replacing the carbazole subunits in the bluish-green BCzBN skeleton with new polycyclic aromatic hydrocarbon (PAH) units, 5-phenyl-5,10-dihydroindolo[3,2-b]indole (IDID) and 5-(4-(tert-butyl)phenyl)-5,10-dihydroindolo[3,2-b]indole (tBuIDID), to simultaneously enlarge the π-conjugation and enhance the electron-donating strength. Consequently, a successful red shift from aquamarine to pure-green is realized for IDIDBN and tBuIDIDBN with photoluminescence maxima peaking at 529 and 532 nm, along with Commission Internationale de l'Eclairage (CIE) coordinates of (0.25, 0.71) and (0.28, 0.70). Furthermore, both emitters revealed narrowband emission with small full width at half-maximum (FWHM) below 28 nm. Notably, the narrowband pure-green emission was effectively preserved in corresponding devices, which afford elevated maximum external quantum efficiencies of 16.3% and 18.3% for IDIDBN and tBuIDIDBN.

Characterization of CM-Dil-labeled Muse cells in culture and in skin wounds in rats.

To investigate the characteristics of multilineage-differentiating stress-enduring (Muse) cells labeled with chloromethyl dialkylcarbocyanine (CM-Dil) in culture and in skin wounds of rats. Normal human dermal fibroblasts (NHDFs) were obtained from foreskins and were confirmed by immunocytochemistry with vimentin. Muse cells were derived from NHDFs using long-term trypsinization (LTT), were confirmed using immunocytochemistry with antibodies against stage specific embryonic antigen-3 (SSEA-3) and CD105 and were expanded in suspension cultures. The Muse cells were labeled with CM-Dil and were further evaluated with respect to their biological properties using CCK-8 assays and scratch tests. One hundred µl CM-Dil-labeled Muse cells at a concentration of 5 × 103/µl were injected subcutaneously at the edges of skin wounds in adult male SD rats. At weeks 1, 3 and 5 after the injection, the distribution of CM-Dil-labeled Muse cells in skin tissues was observed using immunofluorescence microscopy. Muse cells were double-positive for CD105 and SSEA-3. ALP staining of the M-clusters were positive and they displayed orange-red fluorescence after labelling with CM-Dil, which had no adverse effects on their viability, migration or differentiation capacity. One week after the subcutaneous injection of CM-Dil-labeled Muse cells, many cells with orange-red fluorescence were observed at the edges of the skin injuries; those fluorescent spots gradually decreased over time, and only a few Muse cells with fluorescence could be detected by week 5. CM-Dil can be used to label Muse cells without affecting their proliferation, migration or differentiation, and can be used for short-term tracking of Muse cells for the treatment of skin wounds in a rat model.

Force mechanism analysis of composite microbial dust suppressants based on extracellular polymeric substances (EPS) mode components.

As an important potential dust suppression method, the slow onset time is one of the key factors that restrict the effect of microbial dust suppressant. In the early stage, we have confirmed that extracellular polymeric substances (EPS) can improve the dust suppression effect by wetting coal dust and increasing Ca2+ nucleation sites. Therefore, in this study, chitosan (CTS) and bovine serum albumin (BSA) in different ratios (CTS: BSA = 1:1, 1:2, 2:1) as model molecules of EPS were combined with Bacillus subtilis to prepare efficient and fast microbial dust suppressants. Furthermore, the interaction forces were analyzed through molecular dynamics simulation. Results showed that adding CTS and BSA would improve the dust suppression effect, and the dust suppression effect was the best when the ratio of CTS: BSA was 1:2. In addition, the contact angle decreased as the BSA content increased. The Fourier transform infrared spectroscopy (FTIR) results showed that when the ratio of CTS to BSA was 1:2, the dust suppressants were easier to interact with coal dust by the key functional groups and form calcite type CaCO3. The molecular dynamics simulation results showed that the main interaction was Van der Waals force. In addition, the interaction force was strongest when CTS: BSA was 1:2, increasing by 137% compared with the microbial dust suppressants without CTS or BSA. This study provides theoretical support for the development of efficient and rapid microbial dust suppressants.

[Microtubule-associated tumor suppressor 1 inhibits hemin-induced apoptosis of vascular endothelial cells via hemeoxygenase 1].

This study aimed to investigate the effects of microtubule associated tumor suppressor 1 (MTUS1) on hemeoxygenase 1 (HMOX1) expression and hemin-induced apoptosis of vascular endothelial cells and its regulatory mechanism. RNA sequencing, RT-qPCR and Western blot were used to assess altered genes of hemin binding proteins, the expression of cAMP response element-binding protein (CREB) and nuclear respiratory factor 2 (NRF2), hemin-induced HMOX1 expression in MTUS1 knockdown human umbilical vein endothelial cells (HUVEC), and the effect of overexpression of CREB and NRF2 on HMOX1 expression in MTUS1 knockdown 293T cells. The effect of MTUS1 or HMOX1 knockdown on hemin-induced apoptosis in HUVEC, and the overexpression of NRF2 on hemin-induced apoptosis in MTUS1 knockdown 293T cells were assayed with CCK8 and Western blot. The results showed that MTUS1 was knocked down significantly in HUVEC by siRNA (P < 0.01), accompanied by decreased HMOX1 expression (P < 0.01). The increased HMOX1 expression induced by hemin was also inhibited by MTUS1 knockdown (P < 0.01). And the apoptosis of HUVEC induced by hemin was amplified by MTUS1 or HMOX1 knockdown (P < 0.01). Moreover the expression of CREB and NRF2 were both inhibited by MTUS1 knockdown in HUVEC (P < 0.01). The decreased HMOX1 regulated by MTUS1 knockdown could be rescued partly by overexpression of NRF2 (P < 0.01), however, not by overexpression of CREB. And the MTUS1 knockdown mediated decreased 293T cells viability induced by hemin could be partly rescued by NRF2 overexpression (P < 0.01). These results suggest that MTUS1 can inhibit hemin-induced apoptosis of HUVEC, and the mechanism maybe related to MTUS1/NRF2/HMOX1 pathway.

Progress on the role of LIN28A/B in tumor development and progression.

LIN28A and its homolog LIN28B are highly conserved RNA-binding proteins that play important roles in early embryonic development, somatic cell reprogramming, metabolism and tumorigenesis. LIN28A/B are highly expressed in a variety of malignant tumors such as breast cancer. They play important roles in the initiation, maintenance, and metastasis of tumors and are associated with poor prognosis. Previous studies have shown that the main regulatory mechanisms of LIN28A/B include let-7s dependent ways and let-7s independent ways, such as directly targeting mRNA. In this review, we summarize the function and molecular regulatory mechanisms of LIN28A/B in malignant tumors such as liver cancer, breast cancer and colorectal cancer, in order to provide references for further exploring the function and mechanism of LIN28A/B and their possible roles in clinical applications.

Pathoetiology of Levator Ani Syndrome and Its Treatment With Translumbosacral Neuromodulation Therapy.

INTRODUCTION: The pathoetiology and treatment of levator ani syndrome (LAS) remain unclear. METHODS: We evaluated pathophysiology using translumbosacral motor-evoked potentials and anorectal manometry in patients with LAS and compared with healthy controls. A cohort underwent translumbosacral neuromodulation therapy (TNT). RESULTS: Lumbar and sacral motor-evoked potential latencies were prolonged in 32 patients with LAS compared with 31 controls ( P < 0.013), with higher prevalence of anal neuropathy ( P = 0.026). TNT improved anorectal pain ( P = 0.003) and neuropathy ( P < 0.02) in 13 patients with LAS. DISCUSSION: Patients with LAS demonstrate significant lumbosacral neuropathy that may cause anorectal pain. TNT improved anorectal pain and neuropathy, providing a novel therapeutic option.

Formation of Size-Controllable Tetragonal Nanoprisms by Crystallization-Directed Ionic Self-Assembly of Anionic Porphyrin and PEO-Containing Triblock Cationic Copolymer.

The creation of anisotropic nanostructures with precise size control is desirable for new properties and functions, but it is challenging for ionic self-assembly (ISA) because of the non-directional electrostatic interactions. Herein, the formation of size-controllable tetragonal nanoprisms is reported via crystallization-directed ionic self-assembly (CDISA) through evaporating a micellar solution on solid substrates. First, ISA is designed with a crystalline polyethylene oxide (PEO) containing cationic polymer poly(2-(2-guanidinoethoxy)ethyl methacrylate)-b-poly(ethyleneoxide)-b-poly(2-(2-guanidinoethoxy)-ethylmethacrylate) (PGn -PEO230 -PGn ) and an anionic 5,10,15,20-Tetrakis(4-sulfonatophenyl) porphyrin (TPPS) to form micelles in aqueous solution. The PG segments binds excessive TPPS with amplenet chargeto form hydrophilic corona, while the PEO segments are unprecedentedly dehydrated and tightly packed into cores. Upon naturally drying the micellar solution on a silicon wafer, PEO crystallizationdirects the micelles to aggregate into square nanoplates, which are further connected to nanoprisms. Length and width of the nanoprisms can be facilely tuned by varying the initial concentration. In this hierarchical process, the aqueous self-assembly is prerequisite and the water evaporation rate is crucial for the formation of nanostructures, which provides multiple factors for morphology regulating. Such precise size-control strategy is highly expected to provide a new vision for the design of advanced materials with size controllable anisotropic nanostructures.

Follicular fluid progesterone downregulated HPGD and COX2 in granulosa cells via suppressing NF-ĸB in endometriosis†.

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.

Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial.

AIM: Non-surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short-term intensive glucose-lowering therapy. METHODS: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time-to-event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. RESULTS: The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40-0.81; p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14-3.24) and 1.83 (1.03-3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00-3.53) at 48 weeks and 2.05 (0.98-4.29) at 64 weeks. CONCLUSIONS: A 12-week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.

Parkinson's Disease and Diabetes Mellitus: Synergistic Effects on Pathophysiology and GI Motility.

PURPOSE OF REVIEW: Parkinson's disease and diabetes affect an increasing proportion of the aging global population. Both conditions extensively affect gastrointestinal (GI) motility with similar and differing clinical symptoms. Nonetheless, GI symptoms in Parkinson's disease and diabetes pose significant morbidity and impairment of quality of life. Their pathophysiology is poorly understood, and therefore, effective treatment options are lacking. RECENT FINDINGS: Parkinson's disease patients have oropharyngeal dysphagia and constipation. They also have mild or absent upper GI symptoms associated with delayed gastric emptying, which is prevalent in 70% of patients. Delayed gastric emptying in Parkinson's disease leads to erratic medication absorption and fluctuating motor symptoms. Half of diabetics have upper GI symptoms, which correlate to gastric emptying and changes in brain activity of the insular cortex. The majority of diabetics also have constipation. Diabetics have an increased risk for developing Parkinson's disease and anti-diabetic medications are associated with risk reduction of developing Parkinson's disease. Hyperglycemia is associated with advanced glycated end products formation and acceleration of α-synuclein aggregation. GLP-1 receptor agonists have also demonstrated efficacy in improving motor symptoms and cognition in Parkinson's disease patients with diabetes. Parkinson's disease and diabetes are pan-enteric disorders with significant GI symptoms and impairment of gut motility. Both conditions have synergistic pathophysiologies that propagate neurodegenerative changes. Treatment options for GI symptoms in diabetic and Parkinson's disease patients are lacking. Anti-diabetic treatment improves motor symptoms in Parkinson's disease, however, its effect on GI symptoms is unclear.