Explore the vast range of titles available.

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of themyelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.

Delirium is a frequent complication after cardiac surgery and its occurrence is associated with poor outcomes. The purpose of this study was to investigate the impact of perioperative dexmedetomidine administration on the incidence of delirium in elderly patients after cardiac surgery. This randomized, double-blinded, and placebo-controlled trial was conducted in two tertiary hospitals in Beijing between December 1, 2014 and July 19, 2015. Eligible patients were randomized into two groups. Dexmedetomidine (DEX) was administered during anesthesia and early postoperative period for patients in the DEX group, whereas normal saline was administered in the same rate for the same duration for patients in the control (CTRL) group. The primary endpoint was the incidence of delirium during the first five days after surgery. Secondary endpoints included the cognitive function assessed on postoperative days 6 and 30, the overall incidence of non-delirium complications within 30 days after surgery, and the all-cause 30-day mortality. Two hundred eighty-five patients were enrolled and randomized. Dexmedetomidine did not decrease the incidence of delirium (4.9% [7/142] in the DEX group vs 7.7% [11/143] in the CTRL group; OR 0.62, 95% CI 0.23 to 1.65, p = 0.341). Secondary endpoints were similar between the two groups; however, the incidence of pulmonary complications was slightly decreased (OR 0.51, 95% CI 0.26 to 1.00, p = 0.050) and the percentage of early extubation was significantly increased (OR 3.32, 95% CI 1.36 to 8.08, p = 0.008) in the DEX group. Dexmedetomidine decreased the required treatment for intraoperative tachycardia (21.1% [30/142] in the DEX group vs 33.6% [48/143] in the CTRL group, p = 0.019), but increased the required treatment for postoperative hypotension (84.5% [120/142] in the DEX group vs 69.9% [100/143] in the CTRL group, p = 0.003). Dexmedetomidine administered during anesthesia and early postoperative period did not decrease the incidence of postoperative delirium in elderly patients undergoing elective cardiac surgery. However, considering the low delirium incidence, the trial might have been underpowered. ClinicalTrials.gov NCT02267538.

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC. B7H3 is a transmembrane B7 family checkpoint molecule present on many cancer cells. Here the authors show that FUT8 mediates fucosylation of B7H3 to limit the immune response to triple-negative breast cancer as a potentially targeted mechanism of non-responsiveness to current checkpoint therapies.

Improving supply chain sustainability is an essential part of achieving the UN’s sustainable goals. Digitalization, such as blockchain technology, shows the potential to reshape supply chain management. Using distributed ledger technology, the blockchain platform provides a digital system and database to record the transactions along the supply chain. This decentralized database of transactions brings transparency, reliability, traceability, and efficiency to the supply chain management. This paper focuses on such novel blockchain-based supply chain management and its sustainability performances in the areas of environmental protection, social equity, and governance efficiency. Using a systematic literature review and two case studies, we evaluate whether the three sustainability indicators can be improved indirectly along supply chains based on blockchain technology. Our study shows that blockchain technology has the potential to improve supply chain sustainability performance, and we expect blockchain technology to rise in popularity in supply chain management.

The widely used tectonic discrimination diagram, \"Th/Yb-Nb/Yb,\" has long served as a global standard. However, it is limited in scope, as it primarily distinguishes igneous rock samples within well-established tectonic settings, such as nonsubduction environments (e.g. midoceanic ridge and oceanic island basalts) and subduction-related volcanic arcs (e.g. continental and island arcs). This study presents a novel approach to geochemical modeling for Th-Nb-Yb systematics, aimed at enhancing our understanding of various magmatic and tectonic settings. We developed a new geochemical discrimination diagram based on Nb/Yb versus Th/Nb ratios, which successfully identifies and differentiates a wider range of tectonic environments than previous models. Our findings demonstrate that this diagram can distinguish between intracontinental rifting, mixed oceanic-continental rifts producing low-alkaline-enriched tholeiitic magmatism, within-plate continental extensional settings (early lithospheric rifts), and alkaline arcs. Additionally, the model identifies magmatic interactions associated with active continental margin that occur due to oceanic slab break-off. Furthermore, our research refines the use of Th/Yb, Nb/Yb, and La/Yb ratios for improved and more accurate magmatic alkalinity discrimination, enabling clearer differentiation among tholeiitic, calc-alkaline, enriched tholeiitic, and alkaline rock types. These advancements provide a more comprehensive framework for interpreting magmatic processes and their tectonic implications, offering valuable insights to the fields of geochemistry and tectonics.

MicroRNA (miR)-155 is a critical player in both innate and adaptive immune responses. It can influence CD4(+) T cell lineage choice. To clarify the role of miR-155 in CD4(+) CD25(+) regulatory T (Treg)/T helper (Th)17 cell differentiation and function, as well as the mechanism involved, we performed gain-and loss-of-function analysis by transfection pre-miR-155 and anti-miR-155 into purified CD4(+) T cells. The results showed that miR-155 positively regulated both Treg and Th17 cell differentiation. It also induced the release of interleukin (IL)-17A by Th17 cells, but not the release of IL-10 and transforming growth factor (TGF)-β1 by Treg cells. Furthermore, we found that miR-155 reacted through regulating Janus kinase/signal transducer and activator of transcription (JAK/STAT) rather than TGF-β/mothers against decapentaplegic homolog (SMAD) signaling pathway in the process of Treg and Th17 cells differentiation. This may because suppressors of cytokine signaling (SOCS)1, the important negative regulator of JAK/STAT signaling pathway, was the direct target of miR-155 in this process, but SMAD2 and SMAD5 were not. Therefore, we demonstrated that miR-155 enhanced Treg and Th17 cells differentiation and IL-17A production by targeting SOCS1.

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8 + T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors. T cell mediated therapies have proven largely unsuccessful in triple-negative breast cancer (TNBC). Here, the authors show that autophagy is reduced in TNBC, which results in an increase in Tenascin C and reduced activation of tumour infiltrating lymphocytes.

The structure–tissue exposure/selectivity relationship (STR) aids in lead optimization to improve drug candidate selection and balance clinical dose, efficacy, and toxicity. In this work, butyrocholinesterase (BuChE)-targeted cannabidiol (CBD) carbamates were used to study the STR in correlation with observed efficacy/toxicity. CBD carbamates with similar structures and same molecular target showed similar/different pharmacokinetics. L2 and L4 had almost same plasma exposure, which was not correlated with their exposure in the brain, while tissue exposure/selectivity was correlated with efficacy/safety. Structural modifications of CBD carbamates not only changed drug plasma exposure, but also altered drug tissue exposure/selectivity. The secondary amine of carbamate can be metabolized into CBD, while the tertiary amine is more stable. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters can be used to predict STR. Therefore, STR can alter drug tissue exposure/selectivity in normal tissues, impacting efficacy/toxicity. The drug optimization process should balance the structure–activity relationship (SAR) and STR of drug candidates for improving clinical trials.

In many countries, the combination of propofol and opioid is used as the preferred sedative regime during ERCP. However, the most serious risks of propofol sedation are oxygen deficiency and hypotension. Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, and to achieve widespread acceptance for procedural sedation, remimazolam must replace propofol which is the most commonly used for procedural sedation. The objective of this study was to compare the safety and efficacy profiles of the remimazolam and propofol when combined with alfentanil for sedation during ERCP procedures. A randomized, controlled, single-center trial. The Endoscopic Centre of Tianjin Nankai Hospital, China. 518 patients undergoing elective ERCP under deep sedation. Patients scheduled for ERCP were randomly assigned to be sedated with either a combination of remimazolam-alfentanil or propofol-alfentanil. The primary outcome was the prevalence of hypoxia, which was defined as SpO2 < 90% for >10 s. Other outcomes were the need for airway maneuver, procedure, and sedation-related outcomes and side effects (e.g., nausea, vomiting, and cardiovascular adverse events). A total of 518 patients underwent randomization. Of these, 250 were assigned to the remimazolam group and 255 to the propofol group. During ERCP, 9.6% of patients in the remimazolam group showed hypoxia, while in the propofol group, 15.7% showed hypoxia (p = 0.04). The need for airway maneuvering due to hypoxia was significantly greater in the propofol group (p = 0.04). Furthermore, patients sedated with remimazolam had a lower percentage of hypotension than patients sedated with propofol (p < 0.001). Patients receiving remimazolam sedation expressed higher satisfaction scores and were recommended the same sedation for the next ERCP. The procedure time in the remimazolam group was much longer than in the propofol group due to the complexity of the patient's disease, which resulted in a longer sedation time. During elective ERCP, patients administered with remimazolam showed fewer respiratory depression events under deep sedation with hemodynamic advantages over propofol when administered in combination with alfentanil. •The combination of propofol and an opioid is the preferred sedative regime during ERCP.•The major concerns with propofol sedation include oxygen desaturation and hypotension.•Patients administered with remimazolam showed fewer respiratory depression events and hemodynamic advantages over propofol.•These results may provide more options for ERCP sedation.

Optical computing with integrated photonics brings a pivotal paradigm shift to data-intensive computing technologies. However, the scaling of on-chip photonic architectures using spatially distributed schemes faces the challenge imposed by the fundamental limit of integration density. Synthetic dimensions of light offer the opportunity to extend the length of operand vectors within a single photonic component. Here, we show that large-scale, complex-valued matrix-vector multiplications on synthetic frequency lattices can be performed using an ultra-efficient, silicon-based nanophotonic cavity acousto-optic modulator. By harnessing the resonantly enhanced strong electro-optomechanical coupling, we achieve, in a single such modulator, the full-range phase-coherent frequency conversions across the entire synthetic lattice, which constitute a fully connected linear computing layer. Our demonstrations open up the route toward the experimental realizations of frequency-domain integrated optical computing systems simultaneously featuring very large-scale data processing and small device footprints. Synthetic frequency dimension from light modulation enables scalable optical computing. The authors show an efficient silicon-based acousto-optic modulator that generates large synthetic frequency lattices and performs matrix-vector multiplications.