ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.

The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.

Stabilization of the Neutral [25]Hexaphyrin(1.0.1.0.1.0) Radical by Hetero-Bimetal-Coordination.

Stabilization of hexaphyrin(1.0.1.0.1.0) (named "rosarin") in its 25π radical state is achieved using a hetero-bimetal-coordination strategy. The antiaromatic BF2 complex B-1 was first synthesized, and then rhodium ion was inserted into B-1 to produce the BF2/Rh(CO)2 mixed complex Rh-B-1 as a highly air-stable radical. The structures of B-1 and Rh-B-1 were determined by single-crystal X-ray diffractions, and the antiaromatic or radical character was identified by various spectroscopy evidence and theoretical calculations. Rh-B-1 exhibits excellent redox properties, enabling amphoteric aromatic-antiaromatic conversion to their 24/26π states. Compared to the 24/26π conjugation systems on the same skeleton, Rh-B-1 has the narrowest electrochemical and optical band gaps, with the longest absorption band at 1010 nm. The ring-current analysis reveals intense paratropic currents for B-1 and co-existing diatropic-paratropic currents for Rh-B-1. This hetero-bimetal-coordination system provides a novel platform for organic radical stabilization on porphyrinoids, showing the prospect of modulating ligand oxidation states through rational coordination design.

Synthesis of Hybrid Porphyrin(2.1.2.1)s and Their Complexation.

Novel hybrid porphyrin(2.1.2.1)s and their boron and copper complexes were synthesized using the "toy bricks" synthetic method. Crystal data, frontier molecular orbital calculations, and electrostatic potential surface maps reveal that hybridization in the porphyrin(2.1.2.1) donor-acceptor unit controls the selective coordination of BF2.

Electrocatalytic Oxygen Reduction Reaction of Peripheral Functionalized Cobalt Porphyrins(2.1.2.1).

Two peripheral functionalized clamp-shaped cobalt porphyrin(2.1.2.1) complexes were synthesized, and their electrocatalytic ORR abilities were investigated. The crystal data and optical and redox properties of them were revised by peripheral modification. The ORR capacities and DFT calculations of F5PhCo and F5NCo suggest superior selectivity for the 4e- ORR pathway. This work further confirms the clamp-shaped cobalt porphyrin complexes are ideal Co-N4 ORR catalysts.

Construction and application of procedural pathways combined with information management in nursing staff skills training system.

OBJECTIVE: To explore the application effect of procedural pathways combined with information management in the construction of nursing staff skills training system. METHODS: This was a quasi-experimental study with a control group and an experimental group. A total of 300 newly admitted nurses or nurses who required training within three years of admission were selected as the experimental group, and 267 nurses who were trained in the same hospital during the same period in 2020 were selected as the control group. The experimental group received skills training using a system that combines procedural pathways with information management, while the control group received traditional teaching mode. The outcome measures included theoretical score, operation score, nurse competency, patient satisfaction, and nursing-related adverse events. The data were analyzed using t-test, chi-square test, and rank-sum test. RESULTS: The experimental group had higher scores in theoretical assessment, skills assessment, nurse competency, and patient satisfaction, and lower incidence of nursing-related adverse events than the control group (P < 0.05). CONCLUSION: The strategy of procedural pathways combined with information management provides a new perspective and method for nursing operation skills training, effectively improves clinical nursing quality and ensures patient safety.

The microglial innate immune receptors TREM-1 and TREM-2 in the anterior cingulate cortex (ACC) drive visceral hypersensitivity and depressive-like behaviors following DSS-induced colitis.

Inflammatory bowel disease (IBD) is a chronic condition with a high recurrence rate. To date, the clinical treatment of IBD mainly focuses on inflammation and gastrointestinal symptoms while ignoring the accompanying visceral pain, anxiety, depression, and other emotional symptoms. Evidence is accumulating that bi-directional communication between the gut and the brain is indispensable in the pathophysiology of IBD and its comorbidities. Increasing efforts have been focused on elucidating the central immune mechanisms in visceral hypersensitivity and depression following colitis. The triggering receptors expressed on myeloid cells-1/2 (TREM-1/2) are newly identified receptors that can be expressed on microglia. In particular, TREM-1 acts as an immune and inflammatory response amplifier, while TREM-2 may function as a molecule with a putative antagonist role to TREM-1. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we found that peripheral inflammation induced microglial and glutamatergic neuronal activation in the anterior cingulate cortex (ACC). Microglial ablation mitigated visceral hypersensitivity in the inflammation phase rather than in the remission phase, subsequently preventing the emergence of depressive-like behaviors in the remission phase. Moreover, a further mechanistic study revealed that overexpression of TREM-1 and TREM-2 remarkably aggravated DSS-induced neuropathology. The improved outcome was achieved by modifying the balance of TREM-1 and TREM-2 via genetic and pharmacological means. Specifically, a deficiency of TREM-1 attenuated visceral hyperpathia in the inflammatory phase, and a TREM-2 deficiency improved depression-like symptoms in the remission phase. Taken together, our findings provide insights into mechanism-based therapy for inflammatory disorders and establish that microglial innate immune receptors TREM-1 and TREM-2 may represent a therapeutic target for the treatment of pain and psychological comorbidities associated with chronic inflammatory diseases by modulating neuroinflammatory responses.

The circadian regulation of extracellular ATP.

Extracellular ATP is a potent signaling molecule released from various cells throughout the body and is intimately involved in the pathophysiological functions of the nervous system and immune system by activating P2 purinergic receptors. Recent increasingly studies showed that extracellular ATP exhibits circadian oscillation with an approximately 24-h periodicity, which participates in regulatory pathways of central oscillator suprachiasmatic nucleus and peripheral oscillator bladder, respectively. Oscillators modulate the protein expression of ATP release channels and ectonucleotidase activity through clock genes; indeed, real-time alterations of ATP release and degradation determine outcomes of temporal character on extracellular ATP rhythm. The regulatory pathways on extracellular ATP rhythm are different in central and peripheral systems. In this review, we summarize the circadian rhythm of extracellular ATP and discuss several circadian regulatory pathways in different organs via ATP release and degradation, to provide a new understanding for purinergic signaling in the regulatory mechanism of circadian rhythm and a potential target to research the circadian regulation of extracellular ATP in other circadian oscillators.

Red Brick Imperialism: How Vernacular Knowledge Shaped Japanese Colonial Expertise in Northeast China, 1905-45.

This article analyzes the influence and mechanism of Japanese imperialism by examining red brick building in Manchuria (Northeast China). Manchuria's extreme climate and geography led Japanese experts to work with Chinese brick masons. They absorbed Chinese laborers and artisans' vernacular knowledge, translating it into their technical expertise and rebranding it as part of their technological superiority. Studying documents in Russian, Japanese, and Chinese reveals that technology transfer is an interactive yet uneven process between various actors and the environment. This article further complicates the depiction of Japanese imperialism in Northeast China, arguing that imperialism builds on an appropriation and erasure of local knowledge. At the intersection of imperialism and nationalism, red brick became the staple building material in Northeast China, influencing how people build there even today.

First detection and phylogenetic analysis of porcine circovirus 3 in female donkeys with reproductive disorders.

BACKGROUND: PCV3 is a pathogen associated with porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, reproductive failure, and cardiac and multiorgan inflammation, which was newly identified in 2016 in sows in USA. Recently, PCV3 has also been identified from several non-porcine species like (cattle, dog, wild boar, deer, mice and ticks). However, PCV3 infection in donkey is not well established. Since 2019, 300 blood samples were collected from female donkey, which was characterized by abortion and sterility, in Liaocheng city of China. RESULTS: In the present study, an investigation of PCV3 in donkey blood samples was undertaken employing by real time PCR. Positive rates of PCV3 in donkeys reach to 21.0 %. In addition, one full-length PCV3 genome sequence was obtained, and it had a highest identity with porcine circovirus 3 PCV3/CN/Nanjing2017 strain and is clustered to PCV3a genotype based on ORF2 sequences. CONCLUSIONS: This is the first report of detection of PCV3 from female donkeys presenting reproductive failure in large-scale donkey farms, China. In addition, the PCV3 strain identified in this study shared the closest relationship with those from porcine, suggesting that PCV3 may be transmitted from pigs to donkeys. Totally, PCV3 infection in donkey should be concerned although the association between it and reproductive failure are not better understood.

Antimicrobial activity and acting mechanism of Tegillarca granosa hemoglobin-derived peptide (TGH1) against Vibrio parahaemolyticus.

Vibrio parahaemolyticus is a Gram-negative bacterium and the one of leading causal agent of human foodborne diseases such as gastroenteritis upon consumption of raw, or contaminated marine products. There is an increased interest in the use of antimicrobial peptides (AMPs) as alternative food preservatives to prevent foodborne diseases. In this study, bioinformatics tools were used to predict and screen AMPs derived from hemoglobin of blood clam (Tegillarca granosa). A novel AMP, T. granosa hemoglobin-derived peptide (TGH1), was identified and its antimicrobial effect and mechanism of action on V. parahaemolyticus was explored. The minimal inhibitory concentration (MIC) of TGH1 on V. parahaemolyticus was 12.5 µg/mL. Transmission electron microscopy (TEM) revealed that TGH1 kills bacteria by perforating the cell wall perforation and destroying integrity of the cell membrane. Similarly, laser confocal microscopy confirmed that TGH1 entered bacterial cells by aggregating on the cell surface to destroy the cell. In addition, TGH1 increased the inner-membrane permeability of V. parahaemolyticus in a concentration-dependent manner, as well as prevented biofilm formation. Moreover, TGH1 has 55.6% ß-sheet (antiparallel) structure and has no cytotoxic effects on normal human hepatocytes. Thus, peptide TGH1 has good potential use and application in antimicrobial control of foodborne pathogens.

Microwave ablation plus chemotherapy versus chemotherapy in advanced non-small cell lung cancer: a multicenter, randomized, controlled, phase III clinical trial.

OBJECTIVES: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone. MATERIALS AND METHODS: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported. RESULTS: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups. CONCLUSIONS: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone. KEY POINTS: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable.

SOX11: a potentially useful marker in surgical pathology: a systematic analysis of SOX11 expression in epithelial and non-epithelial tumours.

AIMS: SOX11 is known as an essential transcription factor for regulating neurogenesis. Recently, SOX11 has been suggested to be a diagnostic marker and oncogene because of its significant expression in mantle cell lymphoma (MCL). However, SOX11 expression in other tumour types has not yet been extensively studied. METHODS AND RESULTS: Herein, we examined SOX11 expression in 2026 cases of neuroectodermal, germ cell, mesenchymal and epithelial tumours by immunohistochemistry. SOX11 was consistently expressed in all neuroectodermal tumours with neural differentiation, as well as in immature teratomas revealing neurogenesis. Less frequently, SOX11 expression was observed in only 50% of astrocytomas and 24% of malignant peripheral nerve sheath tumours, and was mainly sporadic and weak/intermediate. In epithelial tumours, significant SOX11 expression was identified in 97% of salivary ductal carcinomas (SDCs) and a high percentage of high-grade neuroendocrine carcinomas (NECs), especially the small-cell lung carcinomas (68%), and was absent in most other carcinomas, except for less and/or focal and weak expression in adenocarcinomas from the lung, genital tract and breast, and salivary adenoid cystic carcinomas and epithelial-myoepithelial carcinomas. In mesenchymal tumours, in addition to MCLs, prominent SOX11 expression was observed in 90% of rhabdomyosarcomas and all myxoid/round cell liposarcomas (MRCLs). Less frequent and/or focal and weak expression was observed in lymphoblastic, Burkitt and follicular lymphomas, synovial sarcoma and angiosarcoma. CONCLUSION: SOX11 showed prominent expression in neuroectodermal tumours with neural differentiation, high grade-NEC, SDC, rhabdomyosarcoma and MRCL. The high sensitivity and specificity of SOX11 in SDC and MRCL make it a useful diagnostic marker.

Covid-19 psychological pressures, depression and FOMO: the mediating role of online social support and emotional regulation.

BACKGROUND: The spread of the coronavirus has led to significant anxiety among university students, resulting in various mental health problems that could potentially impact their academic performance. METHOD: To examine the mediating role of emotional regulation and online social support in the relationships between COVID-19 psychological pressures, depression, and the fear of missing out (FoMO) among young adult university students, a cross-sectional research design was employed using an online survey. The sample consisted of 521 full-time university students from China, currently enrolled in undergraduate and postgraduate programs. RESULTS: Findings revealed that more than half (55.09%, n=287) of the university students experienced COVID-19 psychological pressures. These pressures directly contributed to increased levels of depression (ß = 0.339, p < .001) and fear of missing out (ß = 0.236, p < .001). Moreover, online social support and emotional regulation exhibited partial mediating effects on the association between COVID-19 psychological pressures, depression, and the fear of missing out. The results indicated that COVID-19 psychological pressures were linked to higher levels of depressive symptoms and a greater fear of missing out among university students. CONCLUSIONS: However, the provision of timely and adequate online social support, as well as the implementation of emotional regulation strategies, mitigated the negative effects of the pandemic on students' social and emotional well-being. Consequently, this led to reduced levels of depression and fear of missing out.

Distribution and Antimicrobial Resistance Characterization of Listeria monocytogenes in Poultry Meat in Jiading District, Shanghai.

To investigate the distribution, contamination status, and antibiotic resistance of Listeria monocytogenes in four types of retail poultry meat, including chicken, duck, goose, and pigeon, sold in Jiading District, Shanghai, a total of 236 retail poultry meat samples were collected, and L. monocytogenes isolates were obtained for identification and antibiotic susceptibility testing against 14 common antibiotics. Forty-one L. monocytogenes isolates were detected from the 236 retail poultry meat samples, with detection rates of 24.47%, 19.44%, 14.75%, and 4.44% in chicken, goose, duck, and pigeon meat, respectively. Among refrigerated, frozen, and room temperature samples, refrigerated poultry had the highest detection rate at 25.40%, while frozen poultry had the lowest at 13.33%. The detection rate of L. monocytogenes in chicken meat differed significantly between the storage temperatures, while no significant differences were found for other poultry types. No significant differences in detection rates were observed between different retail locations or packaging methods. Isolates exhibited complete resistance to cefoxitin (FOX) and increasing resistance over time to tetracycline (TET) and clindamycin (CLI), while low levels of resistance were found for penicillin (PEN), oxacillin (OXA), and erythromycin (ERY). Resistance to ERY and TET suggests the potential for multidrug resistance. Significant differences in antibiotic resistance profiles were observed among L. monocytogenes from the various poultry types. In summary, contamination status and antibiotic resistance profiles differed among retail chicken, duck, goose, and pigeon meat sold and the resistance rate of strains continues to increase in Jiading District, Shanghai. Targeted control measures should be implemented to reduce the emergence of resistant strains, as retail conditions had minimal impact on L. monocytogenes prevalence in poultry meat.

Benzene-fused porphyrin(2.1.2.1) array: synthesis, structure, and electrocatalytic hydrogen evolution.

The development of efficient molecular catalysts for the electrocatalytic hydrogen evolution reaction (HER) is very necessary and important for fuel cells. In this work, we report a new benzene-fused porphyrin(2.1.2.1) array, BPD, with a unique S-shaped molecular conformation. The electrochemistry of BPD displays multielectron donating and accepting properties owing to the two porphyrin(2.1.2.1) blocks and degenerate molecular orbitals. The electrocatalytic HER activity of BPD is remarkably higher-that is, BPD exhibited lower overpotential, faster HER kinetics, faster charge transfer kinetics, and extended catalytic stability-than that of the porphyrin(2.1.2.1) copper complex monomer.

Porphyrin(2.1.2.1) organopalladium complexes as efficient singlet oxygen sensitizers.

Four new non-planar and non-aromatic porphyrin organopalladium complexes were synthesized. Conformational structures and optical and electronic properties of the obtained organopalladium complexes containing meso-substituted phenyl, p-tert-butylphenyl, or pentafluorophenyl groups were fully investigated. These complexes showed potent capacity for singlet oxygen (1O2) generation under blue-light irradiation, and the 1O2 quantum yields were in the range of 41%-56%, which were comparable to that of Ru(bpy)3Cl2 (57%), and such potency made these organopalladium complexes potential 1O2 photo sensitizers for photodynamic therapy.

Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.

[Molecular cloning and characterization of a novel Clonorchis sinensis antigenic protein containing tandem repeat sequences].

OBJECTIVE: To find and clone new antigen genes from the lambda-ZAP cDNA expression library of adult Clonorchis sinensis, and determine the immunological characteristics of the recombinant proteins. METHODS: The cDNA expression library of adult C. sinensis was screened by pooled sera of clonorchiasis patients. The sequences of the positive phage clones were compared with the sequences in EST database, and the full-length sequence of the gene (Cs22 gene) was obtained by RT-PCR. cDNA fragments containing 2 and 3 times tandem repeat sequences were generated by jumping PCR. The sequence encoding the mature peptide or the tandem repeat sequence was respectively cloned into the prokaryotic expression vector pET28a (+), and then transformed into E. coli Rosetta DE3 cells for expression. The recombinant proteins (rCs22-2r, rCs22-3r, rCs22M-2r, and rCs22M-3r) were purified by His-bind-resin (Ni-NTA) affinity chromatography. The immunogenicity of rCs22-2r and rCs22-3r was identified by ELISA. To evaluate the immunological diagnostic value of rCs22-2r and rCs22-3r, serum samples from 35 clonorchiasis patients, 31 healthy individuals, 15 schistosomiasis patients, 15 paragonimiasis westermani patients and 13 cysticercosis patients were examined by ELISA. To locate antigenic determinants, the pooled sera of clonorchiasis patients and healthy persons were analyzed for specific antibodies by ELISA with recombinant protein rCs22M-2r and rCs22M-3r containing the tandem repeat sequences. RESULTS: The full-length sequence of Cs22 antigen gene of C. sinensis was obtained. It contained 13 times tandem repeat sequences of EQQDGDEEGMGGDGGRGKEKGKVEGEDGAGEQKEQA. Bioinformatics analysis indicated that the protein (Cs22) belonged to GPI-anchored proteins family. The recombinant proteins rCs22-2r and rCs22-3r showed a certain level of immunogenicity. The positive rate by ELISA coated with the purified PrCs22-2r and PrCs22-3r for sera of clonorchiasis patients both were 45.7% (16/35), and 3.2% (1/31) for those of healthy persons. There was no cross reaction with sera of schistosomiasis and cysticercosis patients. The cross reaction with sera of paragonimiasis westermani patients was 1/15. The recombinant proteins rCs22M-2r and rCs22M-3r which only contained tandem repeats were specifically recognized by pooled sera of clonorchiasis patients. CONCLUSION: The Cs22 antigen gene of Clonorchis sinensis is obtained, and the recombinant proteins have certain diagnostic value. The antigenic determinant is located in tandem repeat sequences.

Climate Change, Extreme Temperatures and Sex-Related Responses in Spiders.

Climatic extremes, such as heat waves, are increasing in frequency, intensity and duration under anthropogenic climate change. These extreme events pose a great threat to many organisms, and especially ectotherms, which are susceptible to high temperatures. In nature, many ectotherms, such as insects, may seek cooler microclimates and 'ride out´ extreme temperatures, especially when these are transient and unpredictable. However, some ectotherms, such as web-building spiders, may be more prone to heat-related mortality than more motile organisms. Adult females in many spider families are sedentary and build webs in micro-habitats where they spend their entire lives. Under extreme heat, they may be limited in their ability to move vertically or horizontally to find cooler microhabitats. Males, on the other hand, are often nomadic, have broader spatial distributions, and thus might be better able to escape exposure to heat. However, life-history traits in spiders such as the relative body size of males and females and spatial ecology also vary across different taxonomic groups based on their phylogeny. This may make different species or families more or less susceptible to heat waves and exposure to very high temperatures. Selection to extreme temperatures may drive adaptive responses in female physiology, morphology or web site selection in species that build small or exposed webs. Male spiders may be better able to avoid heat-related stress than females by seeking refuge under objects such as bark or rocks with cooler microclimates. Here, we discuss these aspects in detail and propose research focusing on male and female spider behavior and reproduction across different taxa exposed to temperature extremes.