Platypus and echidna genomes reveal mammalian biology and evolution.

Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution1,2. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are shared by the autosomal homologues in humans. Further comparative genomic analyses unravel marked differences between monotremes and therians in haptoglobin genes, lactation genes and chemosensory receptor genes for smell and taste that underlie the ecological adaptation of monotremes.

The tuatara genome reveals ancient features of amniote evolution.

The tuatara (Sphenodon punctatus)-the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana1,2-is an iconic species that is endemic to New Zealand2,3. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes2,4. Here we analyse the genome of the tuatara, which-at approximately 5 Gb-is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing.

Publisher Correction: The tuatara genome reveals ancient features of amniote evolution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in non-small cell lung cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.

Layer-By-Layer Designed Spark-Type AuCuPt Alloy with Robust Broadband Absorption to Enhance Sensitivity in Flexible Detection of Estriol by a Lateral Flow Immunoassay.

Excessive intake of estrogen poses significant health risks to the human body; hence, there is a necessity to develop rapid detection methods to monitor its levels of addition. Gold nanoparticles (AuNPs), commonly utilized as colorimetric signal labels, find extensive application in lateral flow immunoassay (LFIA). However, the detection sensitivity of traditional AuNPs-LFIA is typically constrained by low molar extinction coefficients and reliance on a single signal. Herein, in this work, unique spark-type AuCuPt nanoflowers modified with tannic acid (AuCuPt@TA) were precisely designed by reasonable layer-by-layer element composition and green modification. The obtained AuCuPt displays robust broadband absorption spanning the visible to near-infrared spectrum, showcasing a notable molar extinction coefficient of 2.38 × 1012 M-1 cm-1 and a photothermal conversion efficiency of 48.5%. Based on this, selecting estriol (E3) as a model analyte, colorimetric/photothermal dual-signal LFIA (CLFIA and PLFIA) was developed. Limits of detection (LOD) of the CLFIA and PLFIA were achieved at 0.033 ng mL-1 and 0.021 ng mL-1, respectively, which represent a 9.3- and 14.6-fold improvement compared to the visual LOD of AuNPs-LFIA. Moreover, the application feasibility of the immunoassay was further evaluated in the milk and pork with satisfactory recoveries ranging from 86.21% to 117.91%. Thus, this work has enhanced the performance of LFIA for E3 detection and exhibited enormous potential for other sensing platform construction.

Clinical spectrum of late symptomatic neurosyphilis in China: an 11-year retrospective study.

OBJECTIVES: This study aimed to describe the clinical features of neurosyphilis in Chinese patients in an attempt to find clinical features that are helpful for the early identification of neurosyphilis. METHODS: This retrospective study included people with syphilis who visited Shanghai Skin Disease Hospital between January 2010 and December 2020. Lumbar puncture was performed on those who met the inclusion and exclusion criteria. The diagnosis of neurosyphilis was based on clinical and laboratory findings. The parameters were analysed statistically. RESULTS: Of the 3524 patients with neurosyphilis, 2111 (59.9%) and 1413 (40.1%) were asymptomatic and symptomatic neurosyphilis, respectively. General paresis was the most common type of symptomatic neurosyphilis (46.8%). The clinical manifestations of symptomatic neurosyphilis include psychiatric and neurotic symptoms, among which general paresis predominantly presented as psychiatric symptoms such as affective (66.7%) and memory disorder (72.9%). Tabes dorsalis is often presented as neurotic symptoms. One hundred fifty patients (10.6%) with symptomatic neurosyphilis presented candy signs, a rare and specific neurosyphilis symptom that is common in general paresis. Girdle sensation was presented in 13 patients, mainly with tabes dorsalis, which had not been reported in previous studies. CONCLUSIONS: Notably, the candy sign is identified as a specific symptom of general paresis, while girdle sensations are highlighted as a particular symptom of tabes dorsalis. This is the largest study describing the clinical spectrum of neurosyphilis since the onset of the penicillin era and could help doctors learn more about the disease. A comprehensive description of the possible clinical manifestations of late symptomatic neurosyphilis, particularly highlighting rare symptoms, can identify suspicious patients and prevent diagnostic delays.

Cost-Effectiveness Analysis of Trastuzumab Deruxtecan Versus Trastuzumab Emtansine for Patients With Human Epidermal Growth Factor Receptor 2 Positive Metastatic Breast Cancer in the United States.

OBJECTIVES: To assess the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine as second-line therapy for patients with human epidermal growth factor receptor 2 positive metastatic breast cancer from a US healthcare sector perspective. METHODS: A 3-state partitioned survival model was developed to estimate the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine. For both treatments, modeled patients were administered treatment intravenously every 3 weeks indefinitely or until disease progression. Transition parameters were principally derived from the updated DESTINY-Breast03 phase III randomized clinical trial. Costs include drug costs extracted from Centers for Medicare and Medicaid Services average sales price and administrative, adverse event, and third-line therapy costs derived from published literature, measured in 2022 US dollars. Health utilities for health states and disutilities for adverse events were sourced from published literature. Effects were measured in quality-adjusted life years (QALYs). We conducted both probabilistic sensitivity analysis and comprehensive scenario analysis to test model assumptions and robustness, while utilizing a lifetime horizon. RESULTS: In our base-case analysis, total costs for trastuzumab deruxtecan were $1 266 945, compared with $820 082 for trastuzumab emtansine. Total QALYs for trastuzumab deruxtecan were 5.09, compared with 3.15 for trastuzumab emtansine. The base-case incremental cost-effectiveness ratio was $230 285/QALY. Probabilistic sensitivity analysis indicated that trastuzumab deruxtecan had an 11.1% probability of being cost-effective at a $100 000 per QALY willingness-to-pay threshold. CONCLUSIONS: Despite the higher efficacy of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, our findings raise concern regarding its value at current prices.

Clinical parameter-based prediction model for neurosyphilis risk stratification.

Accurately predicting neurosyphilis prior to a lumbar puncture (LP) is critical for the prompt management of neurosyphilis. However, a valid and reliable model for this purpose is still lacking. This study aimed to develop a nomogram for the accurate identification of neurosyphilis in patients with syphilis. The training cohort included 9,504 syphilis patients who underwent initial neurosyphilis evaluation between 2009 and 2020, while the validation cohort comprised 526 patients whose data were prospectively collected from January 2021 to September 2021. Neurosyphilis was observed in 35.8% (3,400/9,504) of the training cohort and 37.6% (198/526) of the validation cohort. The nomogram incorporated factors such as age, male gender, neurological and psychiatric symptoms, serum RPR, a mucous plaque of the larynx and nose, a history of other STD infections, and co-diabetes. The model exhibited good performance with concordance indexes of 0.84 (95% CI, 0.83-0.85) and 0.82 (95% CI, 0.78-0.86) in the training and validation cohorts, respectively, along with well-fitted calibration curves. This study developed a precise nomogram to predict neurosyphilis risk in syphilis patients, with potential implications for early detection prior to an LP.

Effects of ambient air pollution on the hospitalization risk and economic burden of mental disorders in Qingdao, China.

OBJECTIVE: The aim of this study was to examine the impacts of short-term exposure to air pollutants on hospitalizations for mental disorders (MDs) in Qingdao, a Chinese coastal city, and to assess the corresponding hospitalization risk and economic cost. METHODS: Daily data on MD hospitalizations and environmental variables were collected from January 1, 2015, to December 31, 2019. An overdispersed generalized additive model was used to estimate the association between air pollution and MD hospitalizations. The cost of illness method was applied to calculate the corresponding economic burden. RESULTS: With each 10 µg/m3 increase in the concentration of fine particulate matter (PM2.5) at lag05, inhalable particulate matter (PM10) at lag0, sulfur dioxide (SO2) at lag06 and ozone (O3) at lag0, the corresponding relative risks (RRs) and 95% confidence intervals (CIs) were 1.0182 (1.0035-1.0332), 1.0063 (1.0001-1.0126), 1.0997 (1.0200-1.1885) and 1.0099 (1.0005-1.0194), respectively. However, no significant effects of nitrogen dioxide (NO2) or carbon monoxide (CO) were found. Stratified analysis showed that males were susceptible to SO2 and O3, while females were susceptible to PM2.5. Older individuals (≥ 45 years) were more vulnerable to air pollutants (PM2.5, PM10, SO2 and O3) than younger individuals (< 45 years). Taking the Global Air Quality Guidelines 2021 as a reference, 8.71% (2,168 cases) of MD hospitalizations were attributable to air pollutant exposure, with a total economic burden of 154.36 million RMB. CONCLUSION: Short-term exposure to air pollution was associated with an increased risk of hospitalization for MDs. The economic advantages of further reducing air pollution are enormous.

Shear-strained Pd Single-atom Electrocatalysts for Nitrate Reduction to Ammonia.

Electrochemical nitrate reduction method (NitRR) is a low-carbon, environmentally friendly, and efficient method for synthesizing ammonia, which has received widespread attention in recent years. Copper-based catalysts have a leading edge in nitrate reduction due to their good adsorption of *NO3. However, the formation of active hydrogen (*H) on Cu surfaces is difficult and insufficient, resulting in a large amount of the by-product NO2-. In this work, Pd single atoms suspended on the interlayer unsaturated bonds of CuO atoms formed due to dislocations (Pd-CuO) were prepared by low temperature treatment, and the Pd single atoms located on the dislocations were subjected to shear stress and the dynamic effect of support formation to promote the conversion of nitrate into ammonia. The catalysis had an ammonia yield of 4.2 mol.gcat-1. h-1, and a Faraday efficiency of 90% for ammonia production at -0.5 V vs. RHE. Electrochemical in-situ characterization and theoretical calculations indicate that the dynamic effects of Pd single atoms and carriers under shear stress obviously promote the production of active hydrogen, reduce the reaction energy barrier of the decision-making step for nitrate conversion to ammonia, further promote ammonia generation.

Comparison of the efficacy of Hydroquinone cream versus Hydroquinone cream plus Danggui Shaoyao powder in the treatment of melasma.

Introduction: Melasma is an acquired hypermelanosis and occurs in areas exposed to sunlight. Aim: To investigate the effectiveness of Danggui Shaoyao powder (DSP) as a complementary drug in the treatment of melasma. Material and methods: A total of 40 melasma patients over the age of 18 who met the inclusion criteria entered the study randomly in two DSP + Hydroquinone (DSP + H) and Hydroquinone (H) groups. Results: At the beginning of the study, the average MASI score of the two groups of patients had no statistical difference (DSP + H: 15.79 ±1.01 vs. H: 15.37 ±1.17, p = 0.23). But from the eighth week of treatment, the MASI score of the patients decreased significantly and in the DSP + H group it decreased statistically significantly compared to the H group (DSP + H: 5.83 ±0.97 vs. H: 8.29 ±2.23, p < 0.001 for the eighth week and DSP + H: 3.60 ±0.58 vs. H: 5.52 ±1.73, p < 0.001 for the twelfth week of the treatment). It means after 12 weeks of treatment, the average MASI score of patients in the DSP + H group decreased by 77.26 ±2.70%, but in the grroup H, it decreased by 64.31 ±9.68% (p < 0.001). Dynamic PGA showed that excellent treatment occurred in 65% of the + H group H, but only 20% of the H group (p = 0.01). Conclusions: Oral DSP for 12 weeks along with hydroquinone cream can significantly reduce the MASI score of melasma patients and increase the patients' recovery and satisfaction.

Metabolic Changes Associated With Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration.

BACKGROUND: Cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, certain animals readily regenerate lost myocardium through a process involving dedifferentiation, which unlocks their proliferative capacities. METHODS: We bred mice with inducible, CM-specific expression of the Yamanaka factors, enabling adult CM reprogramming and dedifferentiation in vivo. RESULTS: Two days after induction, adult CMs presented a dedifferentiated phenotype and increased proliferation in vivo. Microarray analysis revealed that upregulation of ketogenesis was central to this process. Adeno-associated virus-driven HMGCS2 overexpression induced ketogenesis in adult CMs and recapitulated CM dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue, and HMGCS2 knockout mice showed impaired cardiac function and response to injury. Finally, we showed that exogenous HMGCS2 rescues cardiac function after ischemic injury. CONCLUSIONS: Our data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to CM injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

The phagocytic role of macrophage following myocardial infarction.

Myocardial infarction (MI) is one of the cardiovascular diseases with high morbidity and mortality. MI causes large amounts of apoptotic and necrotic cells that need to be efficiently and instantly engulfed by macrophage to avoid second necrosis. Phagocytic macrophages can dampen or resolve inflammation to protect infarcted heart. Phagocytosis of macrophages is modulated by various factors including proteins, receptors, lncRNA and cytokines. A better understanding of mechanisms in phagocytosis will be beneficial to regulate macrophage phagocytosis capability towards a desired direction in cardioprotection after MI. In this review, we describe the phagocytosis effect of macrophages and summarize the latest reported signals regulating phagocytosis after MI, which will provide a new thinking about phagocytosis-dependent cardiac protection after MI.

CircRNA circ_POLA2 overexpression suppresses cell apoptosis by downregulating PTEN in glioblastoma.

The oncogenic role of circ_POLA2 has only been explored in lung cancer, whereas the role of which in glioblastoma (GBM) is unclear. Our research explored the involvement of circ_POLA2 in GBM. Circ_POLA2 and phosphatasetensinhomolog (PTEN) mRNA levels in GBM and paired nontumor tissues collected from 58 GBM patients were analyzed by real-time quantitative PCR (RT-qPCR). Circ_POLA2 and PTEN were overexpressed in GBM cells to study their interaction by RT-qPCR and Western blot. The roles of circ_POLA2 and PTEN in regulating GBM cell apoptosis were explored using cell apoptosis assay. Our data revealed that circ_POLA2 was upregulated and PTEN was downregulated in GBM. PTEN showed an inverse correlation to circ_POLA2 across GBM tissues, In GBM cells, circ_POLA2 overexpression decreased PTEN accumulation, but PTEN overexpression failed to significantly affect circ_POLA2 expression. Moreover, PTEN reduced the inhibitory effects of circ_POLA2 on GBM cell apoptosis. Circ_POLA2 is overexpressed in MCL and might promote GBM cell apoptosis through downregulating PTEN.

Oxygen Vacancy Engineering of Fe-Doped NiMoO4 for Electrocatalytic N2 Fixation to NH3.

Electrochemical nitrogen reduction reaction (NRR) is a promising method for ammonia synthesis under ambient conditions. However, the NRR performance is limited to an extremely strong N≡N bond in N2 and the competing hydrogen evolution reaction. Introducing oxygen vacancies (OVs) has been considered as a forceful means to accelerate the sluggish NRR reaction kinetics. Herein, we reported the design of Fe-doped NiMoO4 catalysts for NRR. Fe doping can increase the amount of OVs in the catalyst and contribute to lattice strain enhancement, thereby leading to the improvement of the electron transport rate and catalytic active for NRR. In 0.1 M Na2SO4 solution, the 5% Fe-NiMoO4 catalyst achieves a NH3 yield rate of 15.36 µg h-1 mgcat.-1 and a Faradaic efficiency of 26.85% under -0.5 V versus RHE. Furthermore, the 5% Fe-NiMoO4 catalyst exhibits excellent stability (up to 13 h) during the reaction.

Theoretical study on hydrogen transfer in the dissociation of dimethyl disulfide radical cations.

Hydrogen transfer (HT) is of crucial importance in biochemistry and atmospheric chemistry. Here, HT processes involved in the dissociation reaction of dimethyl disulfide radical cations (DMDS˙+, CH3SSCH3˙+) are investigated using quantum chemical calculations. Four HTs from the C to S atom and one HT from the S to S atom are observed and the most probable paths are proposed in the dissociation channel from DMDS˙+ to CHnS+ (n = 2-4). The mechanisms of all these five HTs are described as hydrogen atom transfer (HAT) and four of them are accompanied by electron transfer (ET). Considering the catalytic effect of water molecules existing in organisms and the atmosphere, five HT processes in the dissociation of the [DMDS + H2O]˙+ complex are further explored, which show lower free energy barriers. With the participation of water molecules acting as a base, two HTs from the C to the S atom, which have the largest decrease in energy barriers, are characterized as concerted proton-coupled electron transfer (cPCET). These results can be extended to understand the mechanism of the HT process during the dissociation of disulfide and help provide a strategy to design a rare cPCET mechanism for the activation of the C-H bond.

Semisynthesis of 22,25-Epoxylanostane Triterpenoids: Structure Revision and Protective Effects against Oxygen-Glucose Deprivation/Reoxygenation Injury in H9c2 Cells.

22,25-Epoxylanostane triterpenoids indicated protective effects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced myocardial injury in a previous study. In order to discover potent cardioprotective agents, 20 22,25-epoxylanostane triterpenoids, including inonotsuoxides A and B, ganodercochlearins A and B, were synthesized from inotodiol (1). The structures of inonotsuoxide B and ganodercochlearin A are revised as 22R,25-epoxylanosta-8-en-3ß,24R-diol (6) and 22S,25-epoxylanosta-7,9(11)-dien-3ß,24R-diol (12) respectively, based on synthesis, spectroscopic data analysis, and X-ray crystallography. Compounds 13-16 and 22 showed potential protective activity against OGD/R-induced injury in H9c2 cells at a concentration of 20 µM. After OGD/R treatment, the most active compounds 13 and 22 at 5 µM increased cell viability by 11.4% and 6.4% respectively, whereas the positive control diazoxide was 14.9% at 100 µM. Flow cytometric analysis and JC-1 staining assay revealed that 13 suppressed OGD/R-induced apoptosis and the mitochondrial membrane potential in H9c2 cells. Compound 13 may serve as a potential lead cardioprotective agent for further development.

Steroidal Saponins from the Rhizomes of Smilax china and Their Inhibitory Effects on Lipopolysaccharide-Induced Proinflammatory Cytokines Expression.

Four new furostanol saponins (1:  - 4: ) and a new pregane-type saponin (5: ) along with six known steroidal saponins (6:  - 11: ) were isolated from the rhizomes of Smilax china. The structures of 1:  - 5: were elucidated by extensive analysis of NMR and HR-ESI-MS data in addition to enzymatic hydrolysis and other chemical methods. Compounds 1, 4: , and 11: showed inhibitory activity against the expression of proinflammatory mediators, inducible nitric oxide synthase, interleukin-1ß, interleukin-6, and tumor necrosis factor-α in lipopolysaccharide-induced RAW264.7 cells. Compound 1: , at a concentration of 20 µM, decreased the production of inducible nitric oxide synthase, interleukin-1ß, interleukin-6, and tumor necrosis factor-α by 36, 62, 72, and 67%, respectively, which is comparable to that of the positive control dexamethasone.

The Role of Large Animal Models in Cardiac Regeneration Research Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.

PURPOSE OF REVIEW: Heart failure leads to high mortality. The failing myocardium cannot often be rescued as heart regeneration is mostly compromised by disease progress. Stem cell therapy is a strategy under development to replace the impaired myocardium for recovery after heart injury. RECENT FINDINGS: Many studies have provided evidence of the beneficial effects of pluripotent stem cell-derived cardiomyocyte (CM) implantation into diseased rodent hearts, but there are still many challenges and limitations to replicating the same effects in large animal models for preclinical validation. In this review, we summarize progress in the use of pluripotent stem cell-derived CMs in large animal models based on three key parameters: species selection, cell source, and delivery. Most importantly, we discuss the current limitations and challenges that need to be solved to advance this technology to the translational stage.

Curdione inhibits ferroptosis in isoprenaline-induced myocardial infarction via regulating Keap1/Trx1/GPX4 signaling pathway.

Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae. The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.