Streptococcus suis 5'-nucleotidases contribute to adenosine-mediated immune evasion and virulence in a mouse model.

Streptococcus suis (S. suis) is an important swine bacterial pathogen and causes human infections, leading to a wide range of diseases. However, the role of 5'-nucleotidases in its virulence remains to be fully elucidated. Herein, we identified four cell wall-anchored 5'-nucleotidases (Snts) within S. suis, named SntA, SntB, SntC, and SntD, each displaying similar domains yet exhibiting low sequence homology. The malachite green reagent and HPLC assays demonstrated that these recombinant enzymes are capable of hydrolysing ATP, ADP, and AMP into adenosine (Ado), with the hierarchy of catalytic efficiency being SntC>SntB>SntA>SntD. Moreover, comprehensive enzymatic activity assays illustrated slight variances in substrate specificity, pH tolerance, and metal ion requirements, yet highlighted a conserved substrate-binding pocket, His-Asp catalytic dyad, metal, and phosphate-binding sites across Snts, with the exception of SntA. Through bactericidal assays and murine infection assays involving in site-mutagenesis strains, it was demonstrated that SntB and SntC collaboratively enhance bacterial survivability within whole blood and polymorphonuclear leukocytes (PMNs) via the Ado-A2aR pathway in vitro, and within murine blood and organs in vivo. This suggests a direct correlation between enzymatic activity and enhancement of bacterial survival and virulence. Collectively, S. suis 5'-nucleotidases additively contribute to the generation of adenosine, influencing susceptibility within blood and PMNs, and enhancing survival within blood and organs in vivo. This elucidation of their integral functions in the pathogenic process of S. suis not only enhances our comprehension of bacterial virulence mechanisms, but also illuminates new avenues for therapeutic intervention aimed at curbing S. suis infections.

Interaction-and-Response Network for Distantly Supervised Relation Extraction.

Distantly supervised relation extraction (DSRE) aims to identify semantic relations from massive plain texts. A broad range of the prior research has leveraged a series of selective attention mechanisms over sentences in a bag to extract relation features without considering dependencies among the relation features. As a result, potential discriminative information existed in the dependencies is ignored, causing a decline in the performance of extracting entity relations. In this article, we focus on going beyond the selective attention mechanisms and propose a new framework termed interaction-and-response network (IR-Net) that adaptively recalibrates the features of sentence, bag, and group levels by explicitly modeling interdependencies among the features on each level. The IR-Net consists of a series of interactive and responsive modules throughout feature hierarchy, seeking to strengthen its power of learning salient discriminative features for distinguishing entity relations. We conduct extensive experiments on three benchmark DSRE datasets, including NYT-10, NYT-16, and Wiki-20m. The experimental results demonstrate that the IR-Net brings obvious improvements in performance when comparing ten state-of-the-art DSRE methods for entity relation extraction.

The impact of global warming on the potential suitable planting area of Pistacia chinensis is limited.

Pistacia chinensis Bunge. is one of the main woody oil crops with a large artificial planting area in China and has important economic and ecological value. Here, based on 237 occurrence data and 22 environmental variables, we explored the potential planting area of P. chinensis in China in the present and future climate change scenarios by using a comprehensive model method. To fully consider the potential planting area of P. chinensis under specific climate change conditions and the limitations of soil conditions, we separately built two niche models to simulate the climate niche and soil demand niche, and then used the intersection of the two models as the result of the comprehensive habitat suitability model, finally, we used land-use data to filter the CHS model result. Our results showed, that under the baseline condition, the potential planting area of P. chinensis covers approximately 0.74 × 106 km2 in China. The future projection showed that the impact of global warming on the potentially suitable planting area of P. chinensis is limited, and most of the existing suitable habitats are not affected by climate change. With increasing temperature, the potential planting area will expand northward and slightly contract in the south margin, and its area will be slightly increased. Therefore, this species has great planting potential in China and should be given priority in the future afforestation plan.

Hypoxia-induced HIF-1α promotes Listeria monocytogenes invasion into tilapia.

HIF-1α is a nuclear transcription factor, and its activity is tightly regulated by the level of available oxygen in cells. Here, we investigated the roles of HIF-1α in the invasion of Listeria monocytogenes into tilapia under hypoxic environments. We found that the expression levels of HIF-1α in examined tissues of hypoxic tilapia were significantly upregulated, indicating that the tissue cells have been in hypoxic conditions. After 24-h infection with L. monocytogenes, we found that bacterial burden counts increased significantly in all examined tissues of hypoxic fish. To explore why the bacterial count increased significantly in the tissues of hypoxic fish, we modulated HIF-1α expression through RNAi technology. The results indicated that c-Met expression levels were positively related to HIF-1α expression. Since c-Met is the receptor of InlB that plays critical roles in the adhesion and invasion of L. monocytogenes, the ∆InlB strain was used to further explore the reason for the significant increase in bacterial counts in hypoxic fish. As expected, the decrease in the adhesion ability of ∆InlB suggested that InlB mediates L. monocytogenes infection in tilapia. After being infected with ∆InlB strain, we found that the bacterial counts in hypoxic fish were not affected by hypoxic conditions or HIF-1α expression levels. These findings indicate that HIF-1α may promote the internalization of InlB by upregulating c-Met expression and therefore contributes to the invasion of L. monocytogenes into hypoxic tilapia. IMPORTANCE Listeria monocytogenes is a zoonotic food-borne bacterial pathogen with a solid pathogenicity for humans. After ingestion of highly contaminated food, L. monocytogenes is able to cross the intestine invading phagocytic and nonphagocytic cells and causes listeriosis. China is the world's largest supplier of tilapia. The contamination rate of L. monocytogenes to tilapia products was as high as 2.81%, causing a severe threat to public health. This study revealed the underlying regulatory mechanisms of HIF-1α in the invasion of L. monocytogenes into tilapia under hypoxic environments. This study will be helpful for better understanding the molecular mechanisms of hypoxic environments in L. monocytogenes infection to tilapia. More importantly, our data will provide novel insights into the prevention and control of this pathogen in aquaculture.

A case report of a patient with first phenotype of papillary thyroid carcinoma and heterochronous multiprimary tumor harboring germline MUTYH Arg19*/Gly286Glu mutations.

MUTYH-associated polyposis (MAP) is an autosomal recessively inherited disease with multiple system tumors mainly in alimentary system. Tumor occurrence of MAP patients is highly heterogeneous in space and time. MAP is associated with germline biallelic mutations in MUTYH. The targeted next­generation sequencing technology and Sanger sequencing are the important methods to screen MUTYH mutations now. Herein, we identified a patient with heterochronous multiprimary tumor carring MUYTH Arg19*/Gly286Glu compound heterozygous mutations. The patient in this case had a first phenotype of thyroid cancer at age 44, which earlier 2 years than the alimentary system cancers. In conclusion, our case report creases the in-depth understanding of the MAP heterogeneous phenotype and further reminds recommendations for improvement of health management and genetic counseling, special treatment plans.

Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis: A case report.

RATIONALE: Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) with a poor prognosis. Osimertinib is a promising option for NSCLC with LM harboring epidermal growth factor receptor (EGFR) mutation. However, therapeutic approaches remain a challenge for osimertinib resistant NSCLCs with LM. Although studies have reported that the first/second-generation EGFR-tyrosine kinase inhibitors were active against osimertinib-resistant NSCLC with EGFR C797S and sensitive mutation (SM), the resistance inevitably occurred due to the development of the EGFR SM/C797S/T790M triple mutations. PATIENT CONCERNS: A 48-year-old woman was diagnosed with stage IV lung adenocarcinoma harboring the EGFR mutation in the combination of chest computed tomography, biopsy and amplification refractory mutation system-polymerase chain. One year and a half after oral administration of osimertinib, the patient progressed to extensive LM. DIAGNOSES: Magnetic resonance images of the brain showed extensive LM. Exfoliated tumor cells from cerebrospinal fluid (CSF) were positive detected by lumbar puncture and the cytology examination. EGFR mutations (exon19 E746_T751delinsI and exon20 C797S) in CSF circulating tumor DNA were detected by next-generation sequencing (NGS). INTERVENTIONS: Pemetrexed (800 mg day 1), cis-platinum (40 mg day 1-3) combined with bevacizumab (400 mg day 1) every 3 weeks were administered to the patient. After 1 cycle, due to optic nerve invasion, erlotinib was applied 150 mg/d combined with previous regimen. The patient continued erlotinib monotherapy after 6 cycles. OUTCOMES: After LM, erlotinib combined with pemetrexed, cis-platinum and bevacizumab were administered to the patient for 4.25 months based on the CSF NGS. Then, the patient continued erlotinib monotherapy and appeared disease progression after 10 months. The overall survival is 35 months. LESSONS: LM is a fatal complication of advanced NSCLC with a poor prognosis. NGS profiling of CSF circulating tumor DNA is important in NSCLC patients with LM and erotinib plus bevacizumab and chemotherapy is a promising option for patients with LM harboring EGFR C797S/SM.

[A Case Report on Successful Third Challenge to the Pemetrexed-based Regimen for Advanced Non-small Cell Lung Cancer].

Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer, with a 5-year survival rate of less than 15%-19%, and more than 80% of the patients with lung cancer have progressed to advanced stage (Stage IIIb-IV) when they are clearly diagnosed. The comprehensive treatment mainly based on chemotherapy as the primary form is now considered as the major therapy method for advanced NSCLC without actionable driver gene mutations. Pemetrexed plus platinum doublet as well as single-agent pemetrexed are respectively the first-line major regimens recommended by guidelines and the second-line optional regimens. Yet the third-line treatment or beyond in advanced NSCLC is not evidence-based but conducted based on patients' previous medications, which is one of the most commonly used clinical methods. As pemetrexed is a multi-target chemotherapy drug with high efficiency but low toxicity, pemetrexed re-challenge strategy in advanced NSCLC is also a reasonable choice. We report one effective individual case that adopted pemetrexed re-challenge strategy in advanced NSCLC for three times, and at the same time conduct the relevant literature review.

Monthly and annual temperature extremes and their changes on the Tibetan Plateau and its surroundings during 1963-2015.

In this study, the spatiotemporal distributions of monthly and annual temperature minima (Tmin) and maxima (Tmax), extreme Tmin and Tmax, the highest (lowest) Tmin (Tmax), frost day (FD), icing day (ID), summer day (SD) and tropical night (TR) at 112 stations and over the ten large river basins on the Tibetan Plateau and its surroundings (TPS) during 1963-2015 are examined. Mann-Kendall test is applied for the trends. The analyses show: the northwest experiences the hottest summer while the central TPS has the coldest winter and most frequent frost and icing days. The northwest (southeast) features the highest (lowest) monthly extreme temperature ranges. The northwest has the most frequent hot summer days, whereas the southeast has the least frequent frost and icing days. The entire TPS displays few tropical nights. Most stations show positive trends for all monthly and annual Tmin and Tmax variables. February displays the most positive trends for both monthly Tmin and Tmax variables while April shows the highest number of stations with decreasing trends in monthly Tmax. The trends of FD and ID are negative, whereas the trends of SU and TR are positive. Over river basins, the trends of monthly Tmin are all positive and statistically significant and the trends of monthly Tmax are all positive except for one negative trend and around 1/3 of the positive trends are statistically significant. Relatively larger increases in monthly Tmin and Tmax are noted for the cold season than the warm. The monthly and annual Tmin variables increase more than Tmax variables.