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Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

旨在为固体碱催化剂催化油脂裂化制备生物基燃料油提供参考，采用共沉淀法制备Mg-Al水滑石，煅烧后作为催化剂，催化菜籽油裂化制备生物基燃料油。采用XRD、FT-IR、SEM等分析方法对催化剂进行表征分析，并通过对其催化油脂裂化液体产物收率、酸值、皂化值的分析，对其催化性能进行评价，同时采用GC-MS分析了液体产物的组成。结果表明：当催化裂化温度为470 ℃，镁铝比为3∶ 1时，液体产物的收率（60.20%）较高，酸值（KOH）（1.1 mg/g）和皂化值(KOH)(9.3 mg/g)较低；催化剂的最佳使用次数为5次；催化剂的镁铝比为3∶ 1时，液体产物的烷烃和烯烃含量较高。煅烧后的Mg-Al水滑石虽然部分结构遭到破坏，但仍具有很高的结晶度和碱活性，在一定程度上提高了生物基燃料油的品质。 In order to provide a reference for the preparation of bio-based fuel oil by oil cracking catalyzed with solid base catalyst, the Mg-Al hydrotalcite was prepared by co-precipitation method, and then was calcined. The calcined Mg-Al hydrotalcite was used as catalyst to produce bio-based fuel oil by oil cracking.The catalyst was characterized by XRD, FT-IR and electron microscope, and its catalytic performance was evaluated by analyzing the yield, acid value and saponification value of liquid product produced by oil cracking. In addition, the composition of the liquid product was analyzed. The results showed that under the conditions of cracking temperature 470 ℃and ratio of magnesium to aluminum in catalyst 3∶ 1, the yield of liquid product(60.20%) was higher, the acid value (1.1 mgKOH/g)and saponification value(9.3 mgKOH/g) of liquid product were lower. The optimal using times of catalyst were 5. The contents of alkanes and olefins in the liquid product were higher when the ratio of magnesium to aluminum in the catalyst was 3∶ 1. Although part of the structure of calcined Mg-Al hydrotalcite was destroyed, it still had high crystallinity and alkali activity, which improved the quality of bio-based fuel oil to a certain extent.

Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD- L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-[kappa]B pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors., Introduction Aurora A, a member of the evolutionarily conserved Aurora serine/threonine kinase family, is an essential mediator for centrosome maturation and separation and for the ultimate formation of the mitotic [...]

Additive human menopausal gonadotropin (HMG)/recombinant luteinizing hormone (r-LH) to follicle-stimulating hormone (FSH) can improve pregnancy outcomes in patients with poor ovarian response during assisted reproductive procedures. However, their effects on patients with normal ovarian response during such procedures are unclear, which formed the aim of this study. Methods: This retrospective study enrolled 456 infertile women who underwent in vitro fertilization or intracytoplasmic sperm injection treatment. Group 1 received FSH; Group 2 received FSH+HMG/r-LH; Group 3 received FSH+HMG+r-LH. Results: The age and Body Mass Index were significantly greater in Group III. The endometrial thickness was greater in Groups II and III, suggesting better endometrial receptivity. Better pregnancy and birth outcomes were seen in Group 3. In sub-cohorts of women older than 32 years old or with overweight/obesity, pregnancy and birth outcomes were also much better in Group 3, albeit without statistical significance. Conclusion: The addition of both HMG and r-LH to FSH may improve the chance of infertile women with normal ovarian responses to have more success in having live birth babies, specifically in those over 32 years of age or with overweight/obese patients who typically face challenges in conceiving and sustaining a pregnancy. [ABSTRACT FROM AUTHOR]

A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of ≤0.125 µg/mL–4.0 µg/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents. [ABSTRACT FROM AUTHOR]

In conclusion, we recommend patients consider inactivated COVID-19 vaccination before commencing IVF/ICSI treatments to reduce the risk of SARS-CoV-2 infection and severe symptoms during pregnancy that may threaten the well-being of both pregnant mothers and their unborn children. Here, the biochemical pregnancy rates, clinical pregnancy rates and early miscarriage rates were not affected by the vaccination status. Effects of COVID-19 vaccination status, vaccine type, and vaccination interval on IVF pregnancy outcomes in infertile couples. Effects of inactivated COVID-19 vaccinations on the IVF/ICSI-ET live birth rate and pregnancy complication in a population of southern China: A retrospective cohort study. [Extracted from the article]

In the event of a public health crisis, highly effective and sustainable antimicrobial materials and equipment will be urgently needed. Here, the preparation is reported by electrospinning of broad‐spectrum antibacterial nanofibers embedded in a photoactive hydrogen‐bonded organic framework (HOF) of rod‐like nanocrystals ≈60 nm in length. The resulting HOF@PVDF‐HFP nanofibers maintain excellent tensile and breathability characteristics while shielding HOF nanocrystals against acid and alkali corrosion. A series of nanofibers embedded with different amounts and types of HOF nanocrystals are prepared to optimize their efficiency of singlet oxygen (1O2) generation. The 0.5 wt.% HOF‐101‐F@PVDF‐HFP nanofibers exhibit the most efficient 1O2 generation that is enhanced by a factor of almost 2 when compared with the HOF‐101‐F microcrystalline powder. The HOF@PVDF‐HFP nanofibers are demonstrated to highly effectively kill pathogens, including viruses, bacteria, and fungi in 30 min under ambient light conditions. [ABSTRACT FROM AUTHOR]

Candida albicans is a typical opportunistic pathogen in humans that causes serious health risks in clinical fungal infections. The construction of mutant libraries has made remarkable developments in the study of C. albicans molecular and cellular biology with the ongoing advancements of gene editing, which include the application of CRISPR-Cas9 and novel high-efficient transposon. Large-scale genetic screens and genome-wide functional analysis accelerated the investigation of new genetic regulatory mechanisms associated with the pathogenicity and resistance to environmental stress in C. albicans. More importantly, sensitivity screening based on C. albicans mutant libraries is critical for the target identification of novel antifungal compounds, which leads to the discovery of Sec7p, Tfp1p, Gwt1p, Gln4p, and Erg11p. This review summarizes the main types of C. albicans mutant libraries and interprets their applications in morphogenesis, biofilm formation, fungus–host interactions, antifungal drug resistance, and target identification. [ABSTRACT FROM AUTHOR]

Oxidized multi-walled carbon nanotube/nano-gold (AuNP-ox-MWCNT) composites with strong electrochemiluminescence (ECL) activity were applied to construct a new ECL immunosensor for the detection of carcinoembryonic antigen (CEA). The immunosensor showed a linear response range of 10–100 ng mL−1 and detection limit of 0.76 ng mL−1 (at a signal-to-noise ratio of 3). The as-developed immunosensor exhibited several advantages, including being simple to fabricate and being label free. The results indicated that ox-MWCNTs as a luminescent material have great application potential in analysis. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: OSW‐1 is a well‐known natural saponin with potent antitumor activities. We have designed and prepared a small library of 22 OSW‐1 analogues with a variety of p‐acylamino‐benzoyl groups installed at C2" of the xylose residue, wherein a regioselective (1→3)‐glycosylation of arabinoside 3,4‐diol has been achieved by manipulation of the protecting groups on the imidate donors. Bioassays lead to new structure‐activity relationships as well as two applicable fluorescent probes, which are found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW‐1 in living cells. [ABSTRACT FROM AUTHOR]

Aurein1.2 is a 13-residue antimicrobial peptide secreted by the Australian tree frog Litoria aurea. In order to improve its stabilities, the helical contents and corresponding biological activities of Aurein1.2 (a series of stapled analogues) were synthesized, and their potential antifungal activities were evaluated. Not surprisingly, the stapled Aurein1.2 peptides showed higher proteolytic stability and helicity than the linear counterpart. The minimum inhibitory concentration (MIC) of ten stapled peptides against six strains of common pathogenic fungi was determined by the microscale broth dilution method recommended by CLSI. Of them, Sau-1, Sau-2, Sau-5, and Sau-9 exhibited better inhibitory effects on the fungi than the linear peptide. These stapled Aurein1.2 peptides may serve as the leading compounds for further optimization and antifungal therapy. [ABSTRACT FROM AUTHOR]

• ECL was adopted as the useful tool to probe the surface defects of SWCNTs. • SWCNTs were etched by HNO 3 into tubular GQD-nanoassemblies emitting ECL. • It was revealed for the first time that ox-SWCNTs consisted of GQDs and graphene. • The t-GQD-NAs have promising applications in ECL sensing and catalysis. Graphene quantum dots (GQDs) as recently emerging 0-D graphitic nanomaterials, have attracted much attention due to their unique optical, electrical and catalytic properties. However, some properties of GQDs, such as very small size, low density, and excellent water-solubility, make it difficult to be separated and immobilized. This may limit the recycle and purification of GQDs, and thus their applications in catalysis and sensing. In this work, we prepared tubular GQD-nanoassemblies (t-GQD-NAs) by etching single-walled carbon nanotubes (SWCNTs) with concentrated HNO 3. The synthesized t-GQD-NAs were characterized by TEM, SEM, XPS, Raman spectroscopy and electrochemiluminescence (ECL) in details. t-GQD-NAs were much shorter and slimmer in morphology, bore more oxygen-containing groups, and had a higher surface defect density compared with SWCNTs. t-GQD-NAs not only maintained good UV absorption property of SWCNTs but also showed strong infrared ECL emission and broad ECL spectrum, verifying that t-GQD-NAs were assembled from GQDs of various sizes and some graphene nanoribbons. This is for the first time that 0-D GQDs were reported to be assembled into 1-D tubular carbon structures. The t-GQD-NAs with abundant surface states and good ECL activity could be easily separated, purified, and immobilized, suggesting their promising applications in ECL sensing and catalysis. [ABSTRACT FROM AUTHOR]

Background: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest. Design: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed. Results: Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positive CTCs, and 60% (21/35) had at least one PD-L1high CTCs. The disease control (DC) rate in PD-L1high patients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1high CTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postive CTC and PD-L1high CTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1high CTCs at baseline had predicative significance for progression free survival (PFS). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time. [ABSTRACT FROM AUTHOR]

Abstract The interaction between TNF-α with TNFR1 triggers important signaling pathways inducing diverse cellular phenomena including inflammation, apoptosis, etc., and is involved in the pathogenesis and progression of numerous autoimmune diseases. The extracellular domain (ECD) of TNFR has been successfully used to clinically treat such TNF-associated diseases. However, large-scale production of these biological material via eukaryotic cell expression systems is usually costly owing to the culture medium and complicated growth conditions. This study aimed to extract pure soluble human TNFR1-ECD and investigate its biological activity, using a prokaryotic expression system. Recombinant vector pMCSG7-TNFR1-ECD was constructed via ligation-independent cloning. The His-tag fusion protein was expressed in E. coli and localized in inclusion bodies. Recombinant TNFR1-ECD was refolded and purified via nickel-affinity chromatography, tag cleavage, followed by cation-exchange chromatography or size-exclusion chromatography. A purity of over 95% and a yield of 9.3 mg protein per liter of bacterial culture media was obtained. The purified protein showed significant affinity of 2.15 nM towards human TNF-α and inhibited TNF-α-mediated cytotoxicity in L929 cells, with an ED 50 of 0.10 μg/ml. It formed a self-associated oligomer with a K D of 1.15 μM, detected via microscale thermophoresis. We thus established a highly efficient approach to construct, express, and purify the recombinant protein of human TNFR1-ECD from a prokaryotic system. The antagonistic bioactivities in vitro indicate this protein as a prospective molecules for drug research against autoimmune diseases characterized by TNF-α overexpression. Highlights • A highly efficient approach was established to obtain the extracellular domain of human TNFR1 from prokaryotic system. • The recombinant protein showed high purity and excellent biological function. • NanoDSF was used to showed the high thermal stability of the recombinant TNFR1 ectodomain. • MST was first used to demonstrate the oligomerization of the recombinant TNFR1 ectodomain. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: OSW‐1 is a well‐known natural saponin with potent antitumor activities. We have designed and prepared a small library of 22 OSW‐1 analogues with a variety of p‐acylamino‐benzoyl groups installed at C2" of the xylose residue, wherein a regioselective (1→3)‐glycosylation of arabinoside 3,4‐diol has been achieved by manipulation of the protecting groups on the imidate donors. Bioassays lead to new structure‐activity relationships as well as two applicable fluorescent probes, which are found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW‐1 in living cells. [ABSTRACT FROM AUTHOR]

2.2 Fabrication of complex films with citric acid To study the crosslinking process, the CA/GG composite film was prepared for FT-IR and thermogravimetric analysis (TGA) tests. To prepare the CA/GG complex-coated mesh, the cleaned SSM was dipped into the abovementioned mixture solution at room temperature for 5 min to allow the solution to completely wet the SSM. To confirm the crosslinking reaction between guar gum and CA, FTIR was used, and the spectra of GG and hCAGG films are shown in Fig. 3b), the intensity of C O and C O peaks considerably increased in the XPS of coated SSM, which may be attributed to the presence of many -OH groups on the GG backbone and the reaction of CA with GG. [Extracted from the article]

Chitosan is attracting increasing attention for biomedical applications because of its biocompatibility. In the present study, raw halloysite nanotubes (RHNTs) were functionalised with (3-aminopropyl) triethoxysilane (APTS) and then a sequence of novel chitosan biofilms were prepared by adding amino-modified halloysite nanotubes (HNTs-NH 2) as a reinforcing material and ethylene glycol diglycidyl ether (EGDE) as a cross-linking agent. The reaction between the APTS and the RHNTs was demonstrated through characterisation of the HNTs-NH 2. Fourier transform infra-red spectroscopy (FTIR) and X-ray diffraction (XRD) results confirmed the interaction of HNTs-NH 2 with chitosan and EGDE. Scanning electron microscopy (SEM) showed a transformation of the surface morphology of the chitosan films. Measurement of the mechanical and thermal properties showed that the nanocomposite films exhibited substantial improvements in tensile strength, elongation at break and thermal stability compared with those of the pure chitosan films. However, the swelling rate of the nanocomposite films decreased upon incorporation of the HNTs-NH 2 and EGDE. In addition, the water vapour transmission rate (WVTR) of the nanocomposite films was also improved. Given the aforementioned results, chitosan nanocomposites are promising biomedical materials. [ABSTRACT FROM AUTHOR]

Abstract: Implantation is the first maternal–embryo crosstalk that only occurs during a finite period called the ‘implantation window’. HOXA10, a homeobox transcription factor, plays an important regulatory role during this period. However, the target genes of HOXA10 involved in implantation and decidualization have not been identified. Using a chromatin immunoprecipitation screen, we identified the p300/CBP-associated factor (p/CAF) as a direct HOXA10 target gene in vivo. Adenovirus-mediated overexpression and siRNA-specific knockdown of HOXA10 altered p/CAF promoter activity via interaction with the three consecutive TTAT element units in human endometrial cells. These results indicate that p/CAF is a novel HOXA10 target gene, and HOXA10 promotes human endometrial development, at least in part, through the regulation of p/CAF gene. [Copyright &y& Elsevier]

Twenty-six novel triazole analogues featuring isoxazole moieties were designed and synthesized by replacing 4-cyanophenylthioazole moiety in ravuconazole with substituted phenylisoxazole methoxyl. The in vitro antifungal activities demonstrate the introduction of isoxazole methoxyl moiety bearing medium side chains is beneficial for retaining the novel compounds antifungal activities. • Novel triazole analogues featuring isoxazole moieties were designed and synthesized. • All compounds showed potent activity against Candida spp. (MICs ≤ 0.5 μg/mL). • The single-crystal data of compound 2 was obtained. • Compound a6 showed excellent inhibitory activity against some Candida spp. (MICs = 0.0313 μg/mL). In order to develop novel antifungal agents, based on our previous work, a series of (2 R ,3 R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1 H -1,2,4-triazol-1-yl) butan-2-ol (a1 - a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC 80 values of 0.0313 μg/mL. In addition, compounds a6 , a9 , a12 , a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC 80 values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6 , a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the main cause of death related to malignant tumors. Since cause-specific mortality can guide clinical decision-making, this study employed the Fine-Gray model based on the Surveillance, Epidemiology, and End Results (SEER) database to identify significantly how socio-economic status influences initial treatment decisions and survival outcomes in patients with lung adenocarcinoma., Objective: The aim of this study was to identify the predictors of lung adenocarcinoma., Methods: The U.S. Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with lung adenocarcinoma between 2000 and 2018. Seventeen thousand four hundred forty-one patients with lung adenocarcinoma were subdivided in four socio-economic tertiles, based on median household income. Cox regression modeling explored the relationship between race, surgery, grading, and median household income on survival outcomes. The study also assessed patient demographic characteristics, age at diagnosis, and surgical interventions., Results: Among 17 441 patients with primary lung adenocarcinoma, the age distribution was as follows: less than 45 years ( n =202, 1.16%), between 45 and 54 years ( n =1121, 6.43%), 55 and 64 years ( n =4252, 24.38%), 65 and 74 years ( n =6357, 36.45%), 75 and 84 years ( n =4426, 25.38%), and more than 84 years ( n =1083, 6.2%). The adjusted hazard ratio (aHR) with 95% CI for ages 65-74 years, 75-84 years, and older than or equal to 85 years were 0.25 (0.11,1.29), 0.40 (0.11,1.50), and 0.72 (0.11,2.05), respectively. Multifactorial Cox regression indicated that the aHR for tumor metastasis was 0.93 (0.03, 2.54), and for patients who did not undergo surgery, it was 1.46 (0.03, 4.31). Grade IV patients exhibited the lowest survival rate [0.66(0.11, 1.93)]. A notable correlation existed between median household income and survival, with distinctly lower survival rates observed in low-income groups., Conclusion: Older patients, especially those who did not undergo surgery and had a higher tumor grade, had significantly reduced survival. Moreover, survival rates for black patients in lower-income brackets were worse than those for white patients in the same financial category., Implications for Practice: The quality of life of lung cancer patients is affected by low-income family., Competing Interests: The authors declare no conflicts of interest in relation to this work.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The optimal dosage of recombinant human luteinizing hormone (r-hLH) and its impact on endometrial thickness (EMT) when administered alongside recombinant human follicle-stimulating hormone (r-hFSH) during controlled ovarian stimulation (COS) for in vitro fertilization/intracytoplasmic sperm injection and embryo transfer are uncertain, which formed the aims of this systematic review and meta-analysis., Method: A search was performed in PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, and Wanfang from its inception to 10 July 2023. Twenty-seven Randomized controlled trials comparing r-hFSH/r-hLH co-treatment with r-hFSH alone during in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) were included. Pooled odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data, with their respective 95% confidence intervals (CI), were generated. Meta-analysis employed fixed-effect or random-effect models based on heterogeneity, using Q-test and I2-index calculations. The main outcomes included EMT on trigger day, clinical pregnancy rate (CPR) and live birth rate (LBR)., Results: r-hFSH/r-hLH significantly increased EMT on trigger day (MD = 0.27; 95% CI, 0.11-0.42; I 2 = 13%), but reduced oocyte number (MD = -0.60; 95% CI, -1.07 to -0.14; I 2 = 72%) and high-quality embryos (MD = -0.76; 95% CI, -1.41 to -0.10; I 2 = 94%) than r-hFSH alone, more pronounced with the gonadotrophin-releasing hormone agonist long protocol. A subgroup analysis showed r-hLH at 75 IU/day increased CPR (OR = 1.23; 95% CI, 1.02-1.49; I 2 = 16%) and EMT on trigger day (MD = 0.40; 95% CI, 0.19-0.61; I 2 = 0%). Participants ≥35 years of age exhibited decreased retrieved oocytes (MD = -1.26; 95% CI, -1.78 to -0.74; I 2 = 29%), but an increase in EMT on trigger day (MD = 0.26; 95% CI, 0.11-0.42; I 2 = 29%)., Conclusion: r-hFSH/r-hLH during COS significantly improved EMT compared to r-hFSH alone. An r-hLH dose of 75 IU/day may be considered for optimal pregnancy outcomes, which still require further clinical studies to support this dosing regime., Systematic Review Registration: [www.crd.york.ac.uk/PROSPERO], identifier [CRD42023454584]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mao, Hou, Feng, Wang, Fei, Zhao, Chen and Cheng.)

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL against Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus , respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K + channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans -infected mice. Taken together, compound D2 will be further investigated as a promising candidate.

Background: The repression or downregulation of programmed death-ligand 1 (PD-L1) can release its inhibition of T cells and activate antitumor immune responses. Although PD-1 and PD-L1 antibodies are promising treatments for diverse tumor types, their inherent disadvantages and immune-related adverse events remain significant issues. The development of small molecule inhibitors targeting the interaction surface of PD-1 and PD-L1 has been reviving, yet many challenges remain. To address these issues, we aimed to find small molecules with durable efficacy and favorable biosafety that alter PD-L1 surface expression and can be developed into a promising alternative and complementary therapy for existing anti-PD-1/PD-L1 therapies., Methods: Cell-based screen of 200 metabolic molecules using a high-throughput flow cytometry assay of PD-L1 surface expression was conducted, and L-5-hydroxytryptophan (L-5-HTP) was found to suppress PD-L1 expression induced by interferon gamma (IFN-γ). Inhibition of PD-L1 induction and antitumor effect of L-5-HTP were evaluated in two syngeneic mouse tumor models. Flow cytometry was performed to investigate the change in the tumor microenvironment caused by L-5-HTP treatment., Results: We discovered that L-5-HTP suppressed IFN-γ-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-γ-induced expression of RTK ligands and thus suppressed phosphorylation-mediated activation of RTK receptors and the downstream MEK/ERK/c-JUN signaling cascade, leading to decreased PD-L1 induction. In syngeneic mouse tumor models, treatment with 100 mg/kg L-5-HTP (intraperitoneal) inhibited PD-L1 expression and exhibited antitumor effect. L-5-HTP upregulated the ratio of granzyme B+ CD8+ activated cytotoxic T cells. An intact immune system and PD-L1 expression was critical for L-5-HTP to exert its antitumor effects. Furthermore, L-5-HTP acted synergistically with PD-1 antibody to improve anticancer effect., Conclusion: Our study illustrated L-5-HTP's inhibitory effect on PD-L1 induction stimulated by IFN-γ in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Marine rare actinomycetes are an important source of secondary metabolites. From a marine-derived actinomycete Nonomuraea sp. MYH522, four new macrolactams, fluvirucins B 7 -B 10 , together with known fluvirucin B 6 were isolated. Their structures were determined based on comprehensive analysis of HRESIMS and NMR spectroscopic data as well as by comparing 13 C NMR resonances and optical rotation values with those for related congeners. Fluvirucins are characterized by a 14-membered macrolactam attached by an aminosugar moiety. The discovery of fluvirucins B 6 -B 10 enriched the N -acetylated derivatives of fluvirucins. The diverse alkyl substituents at C-2 and C-6 implied substrate promiscuity in fluvirucin polyketide biosynthesis. These compounds didn't exhibit any antibacterial or antifungal activities when used alone, which suggested the importance of the free amino group in the antimicrobial activity of fluvirucins. However, fluvirucins B 6 , B 9 , and B 10 showed synergistic antifungal activity with fluconazole against fluconazole-resistant isolates of Candida albicans ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Glassy carbon (GC) as a well-known electrode material has recently been proposed to consist of fullerene-like nanostructures. In order to verify the nanostructures in GC, find more physiochemical properties of GC, and develop sensors based on GC-related carbon nanomaterials, we investigated the morphologies and surface states of GC microspheres (GCMs) and their HNO 3 -oxidized products (ox-GCMs) with scanning electron microscopy (SEM), electrochemiluminescence (ECL), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and electron-paramagnetic resonance (EPR) spectroscopy. Our research results reveal that ox-GCMs rather than raw GCMs have abundant surface states, including many carboxyl groups (-COOH), surface defects (or carbon edges), and C-related dandling bonds. The surface states with a band gap of 2.14 eV endow ox-GCMs with strong cathodic ECL activity in the presence of peroxydisulfate (S 2 O 8 2- ). The ECL behaviors and maximum emission wavelength (580 nm) of ox-GCMs are very similar to those of small-sized graphene quantum dots and fullerene-like nanosheets, verifying that GCMs are essentially 3-D nanomaterials consisting of graphene or fullerene-like carbon nanostructures. It is for the first time that a microsized carbon material was reported to have good ECL activity in aqueous media. Possible mechanisms for surface state formation and ECL reactions are proposed for ox-GCMs, and a promising application of ox-GCMs in ECL immunosensing has been demonstrated by determining prostate specific antigen (PSA) as a model cancer biomarker.

Total synthesis of naturally occurring spirobisnaphthalene palmarumycin CP17 and its methoxy analogues was first achieved through Friedel-Crafts acylation, Wolff-Kishner reduction, intramolecular cyclization, ketalization, benzylic oxidation, and demethylation using the inexpensive and readily available methoxybenzene, 1,2-dimethoxybenzene and 1,4-dimethoxybenzene and 1,8-dihydroxynaphthalene as raw materials. Demethylation with (CH₃)₃SiI at ambient temperature resulted in ring A aromatization and acetal cleavage to give rise to binaphthyl ethers. The antifungal activities of these spirobisnaphthalene derivatives were evaluated, and the results revealed that 5 and 9b exhibit EC50 values of 9.34 µg/mL and 12.35 µg/mL, respectively, against P. piricola.