Case report: A novel perspective on the treatment of primary tracheal small cell carcinoma: a patient's experience with immuno-combined EP therapy and literature review.

Tracheal small cell carcinoma (SCC) is a rare malignancy, for which the optimal treatment strategy has yet to be determined. Currently, treatment largely aligns with the therapeutic guidelines established for small cell lung cancer, although numerous unresolved issues remain. This paper details a case study of a patient with Stage IIIB primary tracheal SCC, who was treated with an immune-combined etoposide-platinum(EP) regimen. This treatment offers valuable insights into innovative approaches for managing such malignancies. Furthermore, the study includes a comprehensive literature review to better contextualize the findings. The patient, admitted on May 2, 2023, had been experiencing persistent symptoms of airway discomfort for 15 days. A bronchoscopy performed on May 4 revealed tracheal SCC, classified as T4N2M0, IIIB. Following the CAPSTONE-1 study's methodology, the patient underwent six cycles of PD-L1(adebrelimab) combined with EP therapy, leading to significant relief of symptoms and the eventual disappearance of the tracheal mass.

Hydrocarbon Accumulation Periods in the Upper Paleozoic Strata of the Western Ordos Basin, China, Based on Fluid Inclusions and Basin Modeling.

The upper Paleozoic strata in the western part of the Ordos Basin have rich oil and gas resources but low exploration levels. These strata were subjected to multiple tectonic events, such as the Caledonian, Hercynian, Indosinian, and Himalayan movements, which led to a relatively complex process of hydrocarbon accumulation in the study area. These strata also have obvious structural segmentation in the north-south direction. However, the accumulation periods of the upper Paleozoic strata in different structural sections of the western Ordos Basin and their differences are poorly understood. A total of 65 sandstone samples from the upper Paleozoic reservoirs in 16 representative wells were selected for fluid inclusion analyses. The results of fluid inclusion analyses, combined with the burial-thermal histories of representative wells, were used to determine the hydrocarbon accumulation periods of the main layers and summarize their patterns in different structural regions and layers. The results show that the formation of fluid inclusions in the main upper Paleozoic strata can be divided into two stages. The first-stage inclusions mainly occur in secondary quartz edges, and the second-stage inclusions mainly occur in healed microcracks. The inclusion types are dominantly hydrocarbon-bearing, brine, and minor nonhydrocarbon gas inclusions. The hydrocarbon components are mostly CH4 and minor asphaltene, and the nonhydrocarbon gases are dominantly CO2 and minor SO2. The homogenization temperatures of the brine inclusions associated with hydrocarbon inclusions in major layers in the study area have a wide distribution and multiple peaks; the main peaks in the central part of a given tectonic area are slightly lower than those in the eastern part, and the main peaks in a given location tend to increase with decreasing burial depth. Hydrocarbon accumulation in the upper Paleozoic strata in the study area mainly occurred in the Early and Middle Jurassic and Early Cretaceous. The Early and Middle Jurassic were the mature oil and gas accumulation periods, and the Early Cretaceous was the high-maturity natural gas accumulation period and the most critical accumulation period. The accumulation period in the central part of a given structural region occurred earlier than that in the eastern part, and the accumulation period in different layers in a given location gradually shifted at a later time from deep to shallow.

Engineered bacteria producing aryl-hydrocarbon receptor agonists protect against ethanol-induced liver disease in mice.

BACKGROUND AND PURPOSE: Gut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole-3-acetic acid are reduced in patients with alcohol-associated hepatitis. Supplementation of indole-3-acetic acid protects against ethanol-induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl-hydrocarbon receptor (Ahr) agonists. METHODS: C57BL/6 mice were subjected to chronic-plus-binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN-Ahr. The effects of EcN and EcN-Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)-producing cells. RESULTS: Through the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback-resistant tryptophan biosynthesis operon, EcN-Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole-3-acetic acid and indole-3-lactic acid. EcN-Ahr ameliorated ethanol-induced liver disease in C57BL/6 mice. EcN-Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22-expressing type 3 innate lymphoid cells. In addition, EcN-Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN-Ahr was abrogated in mice lacking Ahr expression in Il22-producing immune cells. CONCLUSIONS: Our findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr-mediated activation in intestinal immune cells.

Integrated Proteomic and N-Glycoproteomic Profiling of Placental Tissues of Patients with Preeclampsia.

Background: Preeclampsia (PE) is a multi-system disorder of pregnancy that poses a serious threat to maternal and perinatal health worldwide. This study aims to evaluate the global alterations of protein expression and N-glycosylations that are crucial for PE pathogenesis. Here, tandem mass tag labeling combined with LC-MS/MS was employed to determine the global expression of all proteins and intact glycopeptide in placentas from three healthy pregnant women, three patients with early-onset severe PE, and three patients with late-onset severe PE. Results: A total of 2260 proteins were quantified across 9 placental tissues, of which 37 and 23 were differentially expressed in the early-onset and late-onset PE groups, compared to the controls. A total of 789 glycopeptides were accurately quantified, which were derived from 204 glycosylated sites in 159 glycoproteins and were modified by 59 N-Linked glycans. A total of 123 differently expressed glycopeptides, which were from 47 glycoproteins were identified among three groups. Through a combined analysis of proteomic and glycoproteomic data, it was found that the changes in 10 glycoproteins were caused by the difference in glycosylation level but not in the protein abundance level. Conclusion: This is the first study to conduct an integrated proteomic and glycoproteomic characterization of placental tissues of PE patients. Our findings suggest that glycosylation modification may affect the molecular function of proteins through changes in the glycosylation structure or the occupancy of glycosylation, which will provide new insights to help elucidating the pathogenic mechanism of PE.

Magnetoresistance reversals and anomalous Hall effect in Mn3SnC and effects of carbon deficiency.

The transport behavior of Mn3SnC and Mn3SnC0.8compounds was investigated. Positive magnetoresistance (MR) and an anomalous Hall effect (AHE) are observed for each compound near respective Curie temperature,TC. The positive MR is reversed during cooling fromTCbut is reentrant at low temperature. A 20% carbon deficiency of Mn3SnC0.8enlarges the positive MR atTCand shifts the temperatures for MR reversals. Ferromagnetic (FM) resonance measurements reveal that the MR reversals are related to the competition between FM and antiferromagnetic components of Mn atoms in each compound. A sign change of the Hall resistivity is observed during cooling of Mn3SnC but not for Mn3SnC0.8. A scaling analysis suggests that the AHE in each compound is mostly due to an intrinsic contribution and that the intrinsic contribution is decreased by the carbon deficiency in Mn3SnC0.8.

An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria.

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non-human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.

Associations between AGT, MTHFR, and VEGF gene polymorphisms and preeclampsia in the Chinese population.

INTRODUCTION: Preeclampsia (PE) is a pregnancy-specific multisystemic syndrome. This study aimed to investigate the associations between angiotensinogen (AGT), methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF) polymorphisms, and PE in the Han Chinese population. METHODS: We genotyped 26 single-nucleotide polymorphisms (SNP) in three genes by using QuantStudio™ 12 K Flex Real-Time PCR technology in 168 patients with PE and 204 healthy pregnant control subjects. The associations of tested polymorphisms with PE were analyzed at allele, genotype, and haplotype levels. RESULTS: A common coding variant in MTHFR, rs2274976, was significantly associated with increased risk of PE in both allelic and genotype models (P < 0.05). The heterozygous genotypes of rs699 (G/A vs G/G) in AGT gene and rs3025035 (C/T vs C/C) in VEGF gene showed weak associations with increased PE risk, whereas the mutant homozygous genotype of rs3024987 (TT vs C/C) and the heterozygous genotype of rs3025039 (C/T vs C/C) in VEGF gene displayed weak associations with decreased PE risk (P < 0.05). DISCUSSION: However, these weak associations lost significance after multiple testing correction. The results indicated that rs2274976 in MTHFR gene may contribute to the increased risk of PE in pregnant women. AGT and VEGF gene polymorphisms may not play a significant role in PE development.

4.7 THz asymmetric beam multiplexer for GUSTO.

A full demonstration of the Fourier phase grating used as 4.7 THz local oscillator (LO) multiplexer for Galactic/Extragalactic ULDB Spectroscopic Terahertz Observatory (GUSTO) is presented in this paper, including its design, modeling, tolerance analysis, and experimental characterizations of the angular and intensity distributions among 2 × 4 output beams and the power efficiency. A quantum cascade laser (QCL) is used to generate the input beam for evaluation of the grating performance in its all relevant aspects with an accuracy level never reported before, where good agreements with modeling results are found. This is the first asymmetric-profile grating fully modelled and characterized at a THz frequency, that further confirms the versatility of this technology for providing an intermediate optical element for feeding multiple array detectors with a single radiation source at such a scientifically interesting frequency regime.

Effects of Overwintering on the Survival and Vector Competence of Aedes albopictus in the Urban Life Cycle of Dengue Virus in Guangzhou, China.

The Pearl River Delta, where Aedes albopictus (Ae. albopictus) is the only vector for dengue transmission, has exhibited one of the highest dengue burdens in southern China in recent decades. However, whether dengue virus (DENV) can overwinter in Ae. albopictus in the Pearl River Delta has not been determined to date. In this study, 300 field-derived Ae. albopictus mosquitoes from Guangzhou that were infected with the predominant endemic DENV-1 strain were investigated under simulated urban balcony environment from October 16, 2016, to June 16, 2017. The vertical transmission of DENV in the infected overwintering Ae. albopictus was analyzed. The DENV infected overwintering mosquitoes were evaluated for viral load at nine-time points using reverse transcription-quantitative PCR. The vector competence of the infected overwintering Ae. albopictus was also investigated by using suckling mice. Adult mosquitoes and larvae were found during the observation period. The vertical transmission of DENV-1 was documented. The DENV-1-positive rates between overwintering males and females had no difference. The proportion of DENV-1-positive overwintering mosquitoes decreased over time and had no difference beyond three months after the experiment. Overwintering mosquitoes can spread DENV-1 to hosts. No engorged mosquitoes at an ambient temperature below 15 °C were observed. The ratio of engorged mosquitoes was positively correlated with the ambient temperature ranging from 15 to 30 °C. Our results demonstrated that DENV can overwinter in Ae. albopictus in the Pearl River Delta, Ae. albopictus is the competent vector for DENV, and maintain autochthonous dengue outbreaks in the Pearl River Delta through vertical transmission.

3.9 THz spatial filter based on a back-to-back Si-lens system.

We present a terahertz spatial filter consisting of two back-to-back (B2B) mounted elliptical silicon lenses and an opening aperture defined on a thin gold layer between the lenses. The beam filtering efficiency of the B2B lens system is investigated by simulation and experiment. Using a unidirectional antenna coupled 3rd-order distributed feedback (DFB) quantum cascade laser (QCL) at 3.86 THz as the source, the B2B lens system shows 72% transmissivity experimentally with a fundamental Gaussian mode as the input, in reasonably good agreement with the simulated value of 80%. With a proper aperture size, the B2B lens system is capable of filtering the non-Gaussian beam from the QCL to a nearly fundamental Gaussian beam, where Gaussicity increases from 74% to 99%, and achieves a transmissivity larger than 30%. Thus, this approach is proven to be an effective beam shaping technique for QCLs, making them to be suitable local oscillators in the terahertz range with a Gaussian beam. Besides, the B2B lens system is applicable to a wide frequency range if the wavelength dependent part is properly scaled.

Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.

Ferulic acid confers protection on islet ß cells and placental tissues of rats with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) refers to glucose intolerance of variable degree with onset or first recognition during pregnancy. It causes polyhydramnios, ketoacidosis, fetal macrosomia, and neonatal respiratory distress syndrome. The incidence of GDM has greatly increased, hence the search for new interventions that can effectively treat it. The present study investigated the protective effect of ferulic acid on islet ß cells and placental tissues of rats with GDM. Female Sprague Dawley rats (n = 30) were used in this study. The rats were randomly assigned to three groups of 10 rats each: control group, GDM group and ferulic acid group. The rats were fed high-fat diet consecutively for 12 weeks, except those in control group. In addition, ferulic acid group rats received ferulic acid at a dose of 20 mg/kg body weight (bwt) intragastrically daily for 12 weeks. The expressions of insulin signal transduction proteins and inflammatory factors were determined in rat placental tissue. Apoptosis and levels of expression of apoptosis-related proteins were assessed in isolated islet ß cells. The results showed that the expressions of p-IRS1, p-IRS2, p-PI3K, GLUT1, GLUT3, and GLUT4 were significantly reduced by GDM, but were significantly upregulated after treatment with ferulic acid (p < 0.05). The levels of expression of NF-kB, ICAM-1, TNF-α and IL-ß in placental tissues were significantly higher in GDM group than in control group, but were significantly reduced by ferulic acid treatment (p < 0.05). However, the protein expression of visfatin was significantly reduced by GDM, but was significantly increased by ferulic acid treatment (p < 0.05). Apoptosis was significantly promoted by GDM in islet ß cells, but was significantly and concentration-dependently reduced after treatment with ferulic acid (p < 0.05). Gestational diabetes mellitus (GDM) also significantly down-regulated the expression of bcl-2, but markedly upregulated the expressions of bax and caspase-3 (p < 0.05). However, treatment with ferulic acid significantly and concentration-dependently upregulated the expression of bcl-2, but down-regulated bax and caspase-3 protein expressions (p < 0.05). These results indicate that ferulic acid protects ß cells from GDM-induced apoptosis and improves insulin signaling in placenta of female rats with GDM.

Multi-Step Crystallization of Self-Organized Spiral Eutectics.

A method for the solidification of metallic alloys involving spiral self-organization is presented as a new strategy for producing large-area chiral patterns with emergent structural and optical properties, with attention to the underlying mechanism and dynamics. This study reports the discovery of a new growth mode for metastable, two-phase spiral patterns from a liquid metal. Crystallization proceeds via a non-classical, two-step pathway consisting of the initial formation of a polytetrahedral seed crystal, followed by ordering of two solid phases that nucleate heterogeneously on the seed and grow in a strongly coupled fashion. Crystallographic defects within the seed provide a template for spiral self-organization. These observations demonstrate the ubiquity of defect-mediated growth in multi-phase materials and establish a pathway toward bottom-up synthesis of chiral materials with an inter-phase spacing comparable to the wavelength of infrared light. Given that liquids often possess polytetrahedral short-range order, our results are applicable to many systems undergoing multi-step crystallization.

81 supra-THz beams generated by a Fourier grating and a quantum cascade laser.

Large heterodyne receiver arrays (~100 pixel) allow astronomical instrumentations to map more area within limited space mission lifetime. One challenge is to generate multiple local oscillator (LO) beams. Here, we succeeded in generating 81 beams at 3.86 THz by combining a reflective, metallic Fourier grating with an unidirectional antenna coupled 3rd-order distributed feedback (DFB) quantum cascade laser (QCL). We have measured the diffracted 81 beams by scanning a single pyroelectric detector at a plane, which is in the far field for the diffraction beams. The measured output beam pattern agrees well with a simulated result from COMSOL Multiphysics, with respect to the angular distribution and power distribution among the 81 beams. We also derived the diffraction efficiency to be 94 ± 3%, which is very close to what was simulated for a manufactured Fourier grating (97%). For an array of equal superconducting hot electron bolometer mixers, 64 out of 81 beams can pump the HEB mixers with similar power, resulting in receiver sensitivities within 10%. Such a combination of a Fourier grating and a QCL can create an LO with 100 beams or more, enabling a new generation of large heterodyne arrays for astronomical instrumentation.

Design and photoelectric properties of D-A-π-A carbazole dyes with different π-spacers and acceptors for use in solar cells: a DFT and TD-DFT investigation.

Density functional theory (DFT) and time-dependent DFT (TD-DFT) were used to calculate the properties of the carbazole dyes TYZ-1 to TYZ-5, which differed in their π-spacers. The carbazole dyes TYZ-6 and TYZ-7 were then designed; these were based on TYZ-3 (which had 2,2':5',2″-terthiophene as its π-spacer) but had more strongly electron-withdrawing second acceptor groups than TYZ-3. All of these dyes except for TYZ-5 presented quasi-planar conformations, and the calculated energies of their highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) molecular orbitals as well as their HOMO-LUMO gaps (Eg) suggest that these dyes are suitable for use as sensitizers. Lengthening the π-spacer and increasing its degree of conjugation were found to cause the absorption spectrum of the dye to redshift and to facilitate hole injection. The Eg values of TYZ-6 and TYZ-7 were calculated to be smaller than that of TYZ-3 due to the weaker electron-withdrawing power of the second acceptor group in TYZ-3, and the dyes TYZ-2, TYZ-3, TYZ-6, and TYZ-7 presented the smallest Eg values. Local electron excitations following UV-vis absorption led to electronic transitions, particularly HOMO to LUMO transitions (> 94.3% of all transitions). The excited states of these dyes were found to have quasi-planar conformations, although their dihedral angles were smaller than those in the corresponding ground states. The Stokes Shifts calculated for the seven dyes (which ranged from 51.9 to 98.1 nm) suggested that self-absorption was unlikely to occur. Overall, the calculations indicated that the dyes TYZ-2, TYZ-3, TYZ-6, and TYZ-7 are promising candidates for use in dye-sensitized solar cells.

A predominant dengue virus-1 endemic strain and the vector competence of Aedes albopictus from Guangzhou City, China.

INTRODUCTION: Dengue has been a serious public health burden and dengue virus-1 (DENV-1) is the predominant strain in Guangdong province, China. Differences exist in the transmission dynamics amongAedes albopictus and DENV in different geographical regions. However, little is known about the vector competence of indigenous Aedes albopictus for the predominant dengue strain in Guangdong province, China. METHODOLOGY: In this study, the field-derivedAedes albopictus collected from Guangzhou city, Guangdong province were infected with the predominant DENV endemic strain DENV-1 GZ201401 by feeding on serially diluted artificial infectious blood or infected suckling mice. DENV-infected mosquitoes were evaluated for viral load at five-time intervals in three tissues, the head, body and legs using reverse transcription-quantitative PCR (RT-qPCR). The vertical transmission of DENV in Ades albopictus was also analysed. Suckling mice were used to assess the transmission of DENV by Aedes albopictus. RESULTS: There was no difference in infection rates between mosquitoes infected by infected suckling mice or by artificial infectious blood. The proportion of DENV-1 positive mosquitoes increased over time after an infectious blood meal, but there was no difference in the positive rate beyond 7days after the blood meal. The positive rate of DENV-1 infected mosquitoes increased with the DENV titer in the blood meal. Most of the infections the infected mosquitoes were disseminated more than 7 days after imbibing the artificial infectious blood. The median infective doses (MID50) at 7,14,21 and 28 days after artificial infectious blood meal [7, 14, 21 and 28 days post-infection (dpi)] were 7.86 × 107, 1.57 × 107, 6.39 × 106 and 4.96 × 106 TCID50 (50% tissue culture infective dose)/ml, respectively. The mosquitoes can spread DENV-1 GZ201401 to hosts as early as 3 dpi. The vertical transmission of DENV-1 was documented with a cumulative rate of 17.61%. CONCLUSION: Our results demonstrated that Aedes albopictus mosquitoes are competent vectors for DENV-1, and are capable of maintaining autochthonous dengue outbreaks in Guangdong province, China, which may have been promoted by vertical transmission.

Palladium-catalyzed allylation of aminophenol with alkynes to construct C-N bonds.

A method for the allylic alkylation of aminophenol with alkynes was developed using a palladium-catalysed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted allylamines were synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions.

Liquid phase separation in undercooled Cu-Co alloys under the influence of static magnetic fields.

Undercooling of Cu-based alloys often induces metastable liquid phase separation followed by rapid solidification of separated liquids. The rapid solidification can help freeze in the morphology of a higher-melting liquid and eases difficulties in studies of liquid phase separation kinetics. In the present work, the influence of static magnetic fields on liquid phase separation in bulk Cu84Co16 composition was investigated. Inductively melted samples were glass-fluxed, undercooled and solidified under uniform and non-uniform magnetic fields generated by a superconducting magnet. Solidification microstructure of the phase-separated samples was examined using an optical microscope. The imposition of the magnetic fields, both uniform and non-uniform, altered the morphology, segregation pattern and size distribution of Co-rich droplets due to liquid phase separation. The imposition of the non-uniform magnetic fields with positive and negative gradients brought about segregation of the Co-rich droplets at the top and the bottom side of the samples, respectively. Such influence of the static magnetic fields is interpreted by assuming intensification of convective flow and Kelvin force-controlled migration of the Co-rich droplets. This article is part of the theme issue 'Heterogeneous materials: metastable and non-ergodic internal structures'.

Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors.

A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.