Integrated single-cell transcriptome and T cell receptor profiling reveals defects of T cell exhaustion in pulmonary tuberculosis.

Tuberculosis-affected lungs with chronic inflammation harbor abundant immunosuppressive immune cells but the nature of such inflammation is unclear. Dysfunction in T cell exhaustion, while implicated in chronic inflammatory diseases, remains unexplored in tuberculosis. Given that immunotherapy targeting exhaustion checkpoints exacerbates tuberculosis, we speculate that T cell exhaustion is dysfunctional in tuberculosis. Using integrated single-cell RNA sequencing and T cell receptor profiling we reported defects in exhaustion responses within inflamed tuberculosis-affected lungs. Tuberculosis lungs demonstrated significantly reduced levels of exhausted CD8+ T cells and exhibited diminished expression of exhaustion-related transcripts among clonally expanded CD4+ and CD8+ T cells. Additionally, clonal expansion of CD4+ and CD8+ T cells bearing T cell receptors specific for CMV was observed. Expanded CD8+ T cells expressed the cytolytic marker GZMK. Hence, inflamed tuberculosis-affected lungs displayed dysfunction in T cell exhaustion. Our findings likely hold implications for understanding the reactivation of tuberculosis observed in patients undergoing immunotherapy targeting the exhaustion checkpoint.

Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation of NOTCH1 p.E450K.

Background: Neoadjuvant chemotherapy (nCT) combined with surgery is one of the main strategies for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC). However, nearly 40% of patients did not benefit from nCT, and the detection rate of NOTCH1 missense mutation was significantly increased in patients who did not respond to chemotherapy, suggesting that the missense mutation may be related to tumor chemoresistance. We aim to explore the effect of a NOTCH1 missense mutation on cell phenotype, to interpret the biofunctional changes in cell lines with a NOTCH1 missense mutation and to analyze the effect of a NOTCH1 missense mutation on drug resistance in ESCC cell lines. Methods: Sanger sequencing was used to evaluate the exon mutations in the NOTCH1 ligand binding region of candidate ESCC cell lines. After screening, KYSE450 and KYSE140 cells were selected as the research objects, and point mutation cell lines [KYSE140-mutant-type (MT) and KYSE450-MT] were constructed by CRISPR/Cas9 technology. Then, functional experiments were performed with the four cell lines [KYSE450-MT/wild-type (WT) and KYSE140-MT/WT]. The drug resistance of ESCC cell lines was assessed with a drug sensitivity test, and the proliferation, invasion and migration of ESCC lines were evaluated by proliferation test, scratch test and Transwell test. The cell cycle status of ESCC cells was assessed using flow cytometry. Results: Drug sensitivity tests showed that the NOTCH1 p.E450K point mutation caused chemotherapy resistance in KYSE140 and KYSE450 ESCC cell lines. Cell proliferation, Wound scratch and Transwell assays showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, invasion and migration abilities of KYSE140 and KYSE450 cells. Flow cytometry analysis showed that the NOTCH1 p.E450K point mutation caused an increase in KYSE140 and KYSE450 cells in S phase. Conclusions: The NOTCH1 p.E450K point mutation causes chemotherapy resistance in KYSE140 and KYSE450 ESCC cells. Cell functional experiments showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, migration and invasion abilities of KYSE140 and KYSE450 cells and increased the number of cells in S phase.

Construction of Trisubstituted Hydrazones via Base-Mediated Cascade Condensation N-Alkylation.

A practical base-promoted tandem condensation N-alkylation reaction for the formation of trisubstituted hydrazones has been developed employing aldehydes and hydrazines with alkyl halides. Crucially, this reaction successfully overcomes chemoselectivity problems, allowing for the reaction of multiple components in a one-pot manner. Halo- and heterofunctional groups, as well as free hydroxyl and amino groups, are tolerated in this transformation to produce a wide range of trisubstituted hydrazones in good to excellent yields.

The Role of Adjuvant Chemotherapy in the Treatment of Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemotherapy.

Background: The aim of this study was to compare the efficacy of adjuvant chemotherapy after neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma (ESCC). Methods: This retrospective study included patients diagnosed with ESCC at clinical stage T1N1-3M0 or T2-4N0-3M0. Six hundred and eleven patients underwent radical tumor surgical resection after neoadjuvant chemotherapy. Adjuvant chemotherapy was mainly a platinum-based combination regimen. Propensity score matching (PSM) was used to compare adjuvant chemotherapy (AC) vs. postoperative observation (POB) after surgery. Results: A total of 611 patients were eligible, with 381 in the POB group and 230 in the AC group. POB group patients were younger (P=0.046) and at a later stage (ypT3/4: 127 [55%] vs. 177 [46%]), P=0.036; yPN+: 117[51%] vs. 3428[37%], P=0.001) before PSM. After 1:1 PSM, 213 pairs of patients were included in analysis. The 5-year overall survival (OS) was 60.6% and 57.2% in the POB and AC groups, respectively (HR 1.10, 95% CI: 0.80-1.51, P=0.562), and adjuvant chemotherapy did not improve OS compared with postoperative observation. Conclusions: Postoperative adjuvant chemotherapy cannot improve the OS of patients with ESCC after neoadjuvant chemotherapy, but adjuvant chemotherapy tends to benefit ypN+ patients.

The feasibility of a "no tube, no fasting" fast-track recovery protocol after esophagectomy for esophageal cancer patients aged 75 and over.

Objective: For elderly patients aged ≥75 with esophageal cancer, whether surgical treatment is safe and effective and whether it is feasible to use a relatively radical "no tube, no fasting" fast-track recovery protocol remain topics of debate. We conducted a retrospective analysis to shed light on these two questions. Methods: We retrospectively collected the data of patients who underwent McKeown minimally invasive esophagectomy (MIE) combined with early oral feeding (EOF) on postoperative day 1 between April 2015 and December 2017 at Medical Group 1, Ward 1, Department of Thoracic Surgery of our hospital. Preoperative characteristics, postoperative complications, operation time, intraoperative blood loss, duration of anastomotic leakage (day), hospital stay, and survival were evaluated. Results: Twenty-three elderly patients with esophageal cancer underwent surgery with EOF. No significant difference was observed in intraoperative measures. The incidence of postoperative complications was 34.8% (8/23). Two patients (8.7%) were terminated early during the analysis of the feasibility of EOF. For all 23 patients, the mean hospital stay was 11.4 (5-42) days, and the median survival was 51 months. Conclusion: Patients aged ≥75 with resectable esophageal cancer can achieve long-term survival with active surgical treatment. Moreover, the "no tube, no fasting" fast-track recovery protocol is safe and feasible for elderly patients.

The Feasibility of Early Oral Feeding After Neoadjuvant Chemotherapy Combined With "Non-Tube No Fasting"-Enhanced Recovery.

BACKGROUND: This study aimed to investigate the feasibility of early oral feeding (EOF) after neoadjuvant chemotherapy (nCT) combined with "non-tube no fasting"-enhanced recovery after minimally invasive esophagectomy (MIE). METHODS: This retrospective study investigated patients who underwent nCT combined with non-tube no fasting-enhanced recovery after MIE in the Department of Thoracic Surgery, Ward I, of the authors' hospital from January 2014 to August 2017. These patients were divided into an early oral feeding (EOF) group (n = 112) and a late oral feeding (LOF) group (n = 69). The postoperative complications were compared between the two groups. RESULTS: The study enrolled 181 patients (112 patients in the EOF group and 69 patients in the LOF group). No significant differences were found between the two groups in the incidence rates of complications such as anastomotic leakage (P = 0.961), pneumonia (P = 0.450), respiratory failure (P = 0.944), heart failure (P = 1.000), acute respiratory distress syndrome (ARDS) (P = 0.856), and unplanned reoperation (P = 0.440), whereas the time to the first postoperative flatus/bowel movement (P < 0.001) and the postoperative length of stay (P < 0.001) were significantly better in the EOF group than in the LOF group.. CONCLUSIONS: In this study, EOF after nCT combined with non-tube no fasting-enhanced recovery after MIE did not significantly increase complications, but significantly shortened the time to the first postoperative flatus/bowel movement and the postoperative length of stay.

Boosting Benzene Oxidation with a Spin-State-Controlled Nuclearity Effect on Iron Sub-Nanocatalysts.

A fundamental understanding of the nature of nuclearity effects is important for the rational design of superior sub-nanocatalysts with low nuclearity, but remains a long-standing challenge. Using atomic layer deposition, we precisely synthesized Fe sub-nanocatalysts with tunable nuclearity (Fe1 -Fe4 ) anchored on N,O-co-doped carbon nanorods (NOC). The electronic properties and spin configuration of the Fe sub-nanocatalysts were nuclearity dependent and dominated the H2 O2 activation modes and adsorption strength of active O species on Fe sites toward C-H oxidation. The Fe1 -NOC single atom catalyst exhibits state-of-the-art activity for benzene oxidation to phenol, which is ascribed to its unique coordination environment (Fe1 N2 O3 ) and medium spin state (t2g 4 eg 1 ); turnover frequencies of 407 h-1 at 25 °C and 1869 h-1 at 60 °C were obtained, which is 3.4, 5.7, and 13.6 times higher than those of Fe dimer, trimer, and tetramer catalysts, respectively.

Bletilla striata polysaccharide - waterborne polyurethane hydrogel as a wound dressing.

Polysaccharides are widely used in biomedicine because of their unique biological activity, low costs, and easy-to-obtain. In this paper, Bletilla striata polysaccharide (BSP) was integrated into waterborne polyurethane (WPU) to prepare a series of WPU-BSP (WPUB) hydrogels. The hydrogels showed good compressive strength, water absorption and retention ability, which are favorable for wound healing. Among them, the WPUB4 gel has the best comprehensive performances, including a compressive strength of 1.07 MPa, a swelling rate of 16.3, a reasonable WVRT of 2013 g/m2/day, and a long water retention time. About the in vitro biocompatibility, moreover, the WPUB4 hydrogel has a low hemolysis rate of 2.47%, a hydroxyl radical clearance rate of 35.5%, and little cytotoxicity with cell viability of 101.4%. Most importantly, the WPUB hydrogel dressings showed excellent ability in promoting wound healing. Compared to the conventional gauze, the wound surface area of mice treated with WPUB hydrogel was significantly reduced on day 3 after surgery and the wounds were healed on day 7. The new skin had a thicker epidermis and more capillaries. The WPUB hydrogels integrating BSP are promising to function as wound dressings.

Fundus-Vascular Responses to Color Deviation Caused by Non-Oxidative Blue Filtering.

Aims: Short-wavelength blue light damaged retina by the oxidative stress in the retinal pigment epithelial (RPE) cells. Filtering blue light from screen could reduce blue hazard, whereas it inevitably altered color-gamut coverage and color-deviation level. Although abnormal fundus-vascular density (FVD) sometimes indicated fundus disease, few researchers noticed its responses to the variation of color-gamut coverage and color-deviation level. Methods: In this study, we performed cellular experiments and analyzed the RPE cell viabilities (CVs) in spectrums with different blue (455-475 nm) ratios to describe the corresponding oxidative-stress levels. Further, we investigated the effects of color-gamut and deviation on FVD variations during the screen-watching task using human factor experiments with 30 participants (university students, including 17 males and 13 females, 21 to 30 years old). Results: RPE CVs were similar in different spectrums, implying that non-oxidative blue filtering hardly contributed to CV improvement. Color-deviation level seems to induce more significant effects on the visual function compared to color-gamut coverage, and MTF and FVD presents similar variation trends during the visual task. Conclusion: Oxidative-free blue filtering contributed little to decrease retinal oxidative stress yet caused color-deviation increase, which caused significant FVD reduction.

The safety of neoadjuvant chemotherapy combined with non-tube nofasting fast-track surgery for esophageal carcinoma.

Our non-tube no fasting (early oral feeding and no nasogastric tube) fast-track surgery (FTS) was safe and effective to combine with neoadjuvant chemotherapy for McKeown minimally invasive esophagectomy. In addition, the two groups were similar in terms of the recovery time, hospital discharge day, and early resumption of oral feeding. Objectives: To evaluate the safety of early oral feeding (EOF) combined with neoadjuvant chemotherapy (NAC) of esophagectomy. Summary Background Data: Our non-tube no fasting (early oral feeding and no nasogastric tube) fast-track surgery (FTS) was safe and effective for primary surgery esophageal cancer patients. Methods: We retrospectively evaluated consecutive patients who underwent non-tube no fasting and McKeown minimally invasive (MIE). They were divided into two groups: one received NAC, and the other received primary surgery. Complications after the operation, postoperative CRG complications, operative time, operative bleeding, and length of stay were evaluated. Results: Between 01/2014 and 12/2017, there hundred and eighty two consecutive patients underwent MIE with total two-field lymphadenectomy under the non-tube no fasting fast-track surgery program. A total of 137 patients received NAC, and 245 accepted primary surgery. Propensity score matching was used to compare NAC patients with 62 matched patients from each group. The NAC group had a similar number of total complications as the primary surgery group (32.26% in the primary surgery group vs. 25.81% in the NAC group; p=0.429) and had the same median postoperative hospitalization duration (8 days, p=0.723). Conclusions: After McKeown MIE, the patients receiving NAC combined with "non-tube no fasting" FTS had a similar incidence of postoperative complications outcomes as those without NAC. In addition, the two groups were similar in terms of the recovery time, hospital discharge day, and early resumption of oral feeding.

Preemptive analgesia in the "non-tube no fasting" fast track program for resectable esophageal carcinoma.

Background: Surgery is the main treatment for esophageal cancer, but postoperative incision pain seriously reduces patients' quality of life. The aim of this study was to investigate the feasibility and effectiveness of preemptive analgesia of the upper abdomen with ropivacaine in the "non-tube no fasting" fast track recovery program for esophageal carcinoma. Methods: We retrospectively analyzed the medical records of patients who underwent minimally invasive esophagectomy (MIE) from February 2014 to August 2014. Patients in the study group underwent a conventional analgesia program together with local infiltration injection of ropivacaine in the upper abdominal incision 30 min before the operation, while patients in the control group underwent the conventional analgesia program alone. Ropivacaine was injected locally around the planned surgical incision, including intradermally, subcutaneously, in the fascial muscles, and in the parietal peritoneum layers. Li's anastomosis method was performed in the neck after MIE. No indwelling chest tube or abdominal cavity tube was placed in any patients. The use of analgesic pumps in the two groups of patients was recorded. Results: A total of 102 patients were enrolled in the study, with 52 patients in the study group and 50 patients in the control group. Patients in both groups completed the surgery successfully as planned, and the anesthesia methods and drugs used during the operation were the same. The surgical duration, blood loss, and the number of resected lymph nodes did not differ significantly between the two groups. Three patients in the study group and 10 patients in the control group used analgesia pumps (P=0.031). The visual analog scale (VAS) score at 30 days after surgery in the group with preemptive analgesia was significantly better than that in the control group (P=0.048). Conclusions: Preemptive analgesia for the upper abdomen with ropivacaine in the "non-tube no fasting" fast track recovery program for esophageal carcinoma is feasible and worthy of promotion.

The Notch1 gene may control cell chemoresistance in esophageal squamous cell cancer.

BACKGROUND: In our previous study, missense mutations in the Notch1 gene were found in chemotherapy-resistant esophageal squamous cell cancer (ESCC) patients. In this study, we explored changes in the interaction between Notch1 and DLL4 resulting from missense mutations. METHODS: Bioinformatics analysis was performed to assess and compare the different biological structures and functions of wild type (WT) and mutation type (MT) sequences of Notch1. A genetic information search was performed, and the results were analyzed using in silico modeling. Homology modeling of the Notch1 protein was carried out using Swiss-Model software, and modeling of site-directed mutations was carried out using PyMOL software to observe the protein structure. The Notch1-DLL4 ligand-receptor complex protein model was constructed, Wincoot software was used to determine site-directed mutations, and a protein-ligand interaction profiler (PLIP) was used to calculate the noncovalent interactions in the complex. RESULTS: The mutation site was located in the region where Notch1 binds to DLL4. A careful examination of the in silico structural model revealed that the mutation caused an alteration in the surface charge, and the water-bridge bonds of the interaction between Notch1-DLL4 increased in number from 5 to 7. CONCLUSIONS: Notch1 gene missense mutation leads to an increase in the number of water-bridge bonds, thus enhancing the Notch1-DLL4 interaction, which may lead to tighter Notch1-DLL4 binding, either making the pathway easier to activate or increasing the length of time it is active.

Implementation and security analysis of practical quantum secure direct communication.

Rapid development of supercomputers and the prospect of quantum computers are posing increasingly serious threats to the security of communication. Using the principles of quantum mechanics, quantum communication offers provable security of communication and is a promising solution to counter such threats. Quantum secure direct communication (QSDC) is one important branch of quantum communication. In contrast to other branches of quantum communication, it transmits secret information directly. Recently, remarkable progress has been made in proof-of-principle experimental demonstrations of QSDC. However, it remains a technical feat to bring QSDC into a practical application. Here, we report the implementation of a practical quantum secure communication system. The security is analyzed in the Wyner wiretap channel theory. The system uses a coding scheme of concatenation of low-density parity-check (LDPC) codes and works in a regime with a realistic environment of high noise and high loss. The present system operates with a repetition rate of 1 MHz at a distance of 1.5 kilometers. The secure communication rate is 50 bps, sufficient to effectively send text messages and reasonably sized files of images and sounds.

Multiple Stimuli-Responsive Fluorescent Sensor from Citric Acid and 1-(2-Aminoethyl)piperazine.

Multiresponsive fluorescent supramolecular materials are quite interesting, for they combine the multiresponsiveness of supramolecules and the high sensitivity of fluorescent materials. Different from the multiresponsive supramolecular materials based on host-guest interactions, in this report, a supramolecular ionic network was fabricated by 1-(2-aminoethyl)piperazine and citric acids via ionic interactions. Despite the fact that there are no conventional chromophores, the obtained supramolecular ionic material can emit strong fluorescence. Most interestingly, the thin film of this supramolecular ionic material can change its fluorescent intensity in response to four external stimuli, including humidity, triethylamine, acetic acid, and temperature. Beneficial to the supramolecular ionic structure, this multiresponsive fluorescent sensor is self-healable. It is found that a new route has been opened to prepare the multiresponsive fluorescent sensors.

Morphology and pervaporation performance of ionic liquid and waterborne polyurethane composite membranes.

Blending an aromatic-selective ionic liquid (IL, namely 1-ethyl-3-methylimidazolium hexafluorophosphate, [emim][PF6]) with waterborne polyurethane (WPU) enabled us to obtain [emim][PF6]-modified waterborne polyurethane composite membranes. We characterized the structure and properties of the [emim][PF6]/WPU composite membranes by ATR-FTIR, DSC, UV, SEM, EDX, swelling tests, and pervaporation testing. Characterization of the change in the morphology of the membranes in response to the IL loading indicated that a preferential interaction between the IL and soft segments of WPU was induced by hydrogen bonding. This interaction inhibited a potential interaction with benzene (Bz), which initially lowered the permeability. However, at high IL loading, the IL incorporation became ineffective owing to macrophase separation, which caused an increase in the permeability, as indicated by the SEM results. Swelling testing of the [emim][PF6]/WPU composite membranes showed that the membranes exhibited preferential adsorption of Bz, and the swelling degree of the composite membranes in Bz solvent increased from 58% to 98% and remained almost constant in cyclohexane solvent as the IL content was increased. The [emim][PF6]/WPU composite membranes enhanced the separation selectivity of Bz/Cy for an IL loading < 10 wt%. The best separation factor was 8.4, and the total flux was 0.19 kg (m2 h)-1 (50 wt% Bz/Cy mixtures at 50 °C) at w([emim][PF6]) : w(WPU) = 10 : 100. In addition, the composite membrane exhibited excellent stability over long-term operation. These results demonstrated that the [emim][PF6]/WPU composite membranes could be effective for separation of Bz/Cy mixtures by the pervaporation method.

Highly Stretchable Strain Sensors Using an Electrospun Polyurethane Nanofiber/Graphene Composite.

A highly flexible and stretchable strain sensor has been prepared by coating chemical reduction of graphene oxide on electrospun polyurethane nanofiber mats. The sensor exhibits an ohmic behavior regardless of applied strains and the current monotonically increases with the increase of the tensile strain. The morphology and stability of electrospun polyurethane nanocomposite mats were also studied. The flexible and stretchable strain sensor has great potential for practical application such as efficient human-motion detection. This cheap and simple process of graphene layer provides an effective fabrication for graphene stretchable electronic devices and strain sensors due to excellent stability and electrical proper.

Nacrelike Nanocomposite Films from Fluorescent Hyperbranched Poly(amido amine)s and Clay Nanosheets.

Inspired by the hierarchical structure of nacre, lots of functional nanocomposite films have been fabricated through finely tuning the composition and structure. To broaden their application in biological and biomedical research, it is highly demanded to develop a new strategy to fabricate nanocomposite films that are both biocompatible and functional. Herein, hyperbranched poly(amido amine)s (HPAMAMs) have been assembled with clay nanosheets. The obtained nanocomposite films show good mechanical performance and fluorescence properties. Analysis of the structure of the nanocomposite films indicates that the HPAMAMs and the clay nanosheets are stacked together in an orderly manner. The clay nanosheets align in the direction parallel to the film surface. Because of the inherent biocompatibility and autofluorescence property of the HPAMAMs, such composite films are thought to be very promising in applications requiring biocompatibility, fluorescence, and good mechanical performance. The method should provide a new route to the fabrication of functional nacrelike composite materials.