Bacterial biofilms can be viewed as a specific type of persistent bacterial infection. After initial invasion, microbes can attach to living and non-living surfaces, such as prosthetics and ...indwelling medical devices, and form a biofilm composed of extracellular polysaccharides, proteins, and other components. In hosts, bioffim formation may trigger drug resistance and inflammation, resulting in persistent infections. The clinical aspects of biofilm formation and leading strategies for hiofilm inhihitors will be discussed in this mini-review.
Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, ...glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer.
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•GDH1 contributes to anoikis resistance and tumor metastasis by activating CamKK2•α-KG binds to CamKK2 and recruits AMPK to CamKK2•In LKB1 null lung cancer, GDH1-induced CamKK2 substitutes for LKB1 to activate AMPK•PLAG1 induces GDH1 expression upon cell detachment from the matrix
Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis promotes tumor metastasis remains unclear. In this article, Jin et al. demonstrate a mechanism by which GDH1 provides anti-anoikis and pro-metastatic signals through activating CamKK2 and AMPK that promotes tumor metastasis in LKB1-deficient lung cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Leprosy is a chronic infectious disease that causes disabilities and deformities. Early detection is a major strategy for leprosy control. This study reported a new practice of suspicious ...symptom monitoring for early detection of leprosy.
Methods
A descriptive and comparative analysis between a non‐strategy group of pre‐implementation of suspicious symptom monitoring in 2005–2011 and a strategy group of strategy implementation in 2012–2018 was conducted through indicators of the number of times of misdiagnoses, delayed period, proportion of early detected cases, and proportion of disabilities.
Result
Compared with the non‐strategy group in 2005–2011, the median number of times of misdiagnoses was decreased from two times to zero times (z = 4.387, P < 0.001), and the median delayed period of newly detected cases were shortened from 24 months to 13 months (z = 2.381, P < 0.001), the proportion of early detected cases was increased from 43.7% to 75.2% (χ2 = 29.464, P < 0.001), the proportion of grade 2 disabilities was decreased from 28.6% in the highest year of 2005 to 4.0% in the lowest year of 2014, and the average proportion of disabilities was decreased from 33.5% to 17.6% (χ2 = 9.421, P = 0.002) in the strategy group in 2012–2018, respectively.
Conclusion
Suspicious symptom monitoring promoted early detection of cases by reducing the number of times misdiagnosis of leprosy patients, shortening the delayed period, increasing the proportion of early detection, and decreasing the proportion of disabilities. It is an important and recommendable public health strategy for leprosy prevention and control in a low epidemic condition.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This study applied the question-oriented problem-solving (QOPS) pedagogy in Statistics learning and addressed several methodological and theoretical gaps in SNA studies to inform instructional and ...learning implications for teachers and students. The limitations in SNA studies included the lack of theoretical support in the analysis, the homogeneous medium where the data for SNA is collected, the constraints in the diversity of the network modes, and the lack of associations about the SNA measures with learning outcomes. Thus, we investigated 1) how a learning community based on social media evolved with the implementation of the QOPS activities, 2) changes in instructors and learners' roles in light of their one-mode and two-mode SNA measures, and 3) how different relational ties and SNA measures were associated with student outcomes. Participants were 23 graduate students (females: 52.17%) and an instructional team of three. Seven hundred four messages, including 118 posts and 586 comments, were collected from the private advanced statics Facebook learning group over an 18-week advanced Statics course. Aligned with the QOPS approach, the learning community became more interactive and cohesive, as reflected in their one-mode SNA measures. Besides, the two-mode measures, including density, GCC, reciprocity, transitivity, and strong/weak components, demonstrated that the learning community became denser and more interactive via their shared discussion. The instructional team played unique roles as a leader or facilitator in their interaction with students, while students' roles as a leader and coordinator were identified. Students' outdegree, degree, and closeness centralities have the most consistent predictive validity of their learning outcomes. Higher values in degree or closeness via shared discussion topics such as discussion of quizzes, help-seeking, and course administrative communication also predicted performance. The study results have practical implications for instructors and researchers in designing the hybrid learning environment and providing scaffolds to promote help-seeking.
•Interaction analytics confirm the instructional pedagogy in a semester-long course.•Facebook discussion is studied using one-mode and two-mode social network analyses.•Aligned with pedagogies, the learning community gets more interactive and cohesive.•Instructors and students play unique roles as a leader, facilitator, or coordinator.•Suggestion is made for the learning environment design with scaffolded help-seeking.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. ...These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Clinical and experimental preparations of IgG/soluble antigen complexes, as well as those formed following antibody therapy in vivo, are multifaceted immune regulators. These immune complexes (ICs) ...have been tested in humans and animal models, mostly in forms of experimental or clinical vaccination, for at least a century. With intensified research on Fcγ receptor‐mediated immune modulation, as well as with immune complex‐directed antigen processing, presentation, and inflammatory responses, there are renewed interests of using ICs in vaccines and immunotherapies. Currently, IC‐based immune therapy has been broadly experimented in HBV and HIV viral infection control and antitumor treatments. However, mechanistic insights of IC‐based treatments are relatively recent subjects of study; strong efforts are needed to establish links to connect laboratory findings with clinical practices. This review covers the history, mechanisms, and in vivo outcomes of this safe and effective therapeutic tool, with a clear aim to bridge laboratory findings with evolving clinical applications.
This review aims to provide a utilitarian look on immune complexes (ICs) from a perspective of clinical application, to complement the current picture of antibody immune therapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Many researches on gender differences in leprosy found that female patients were detected with the disease later and had more serious disabilities than male patients. We analyzed the ...gender differences related to epidemiological characteristics of new leprosy cases detected from 2000 to 2015 in Sichuan Province, China.
Methods
A retrospective study was undertaken to analyze the gender differences with respect to age, delay in disease detection, the main modes of detection, and disability grade. The chi‐squared test and t test were applied for the comparison using Epi Info 7.2 with a significance level of a = 0.05. The data were collected from the Leprosy Management Information System in China.
Results
A total of 2900 new leprosy cases were detected from 2000 to 2015, of whom 2075 (71.6%) were male and 825 (28.4%) were female with a gender ratio of 2.5. The gender ratio of patients aged 15–30 was significantly lower than that of patients aged 31–45 and 46–60. Male cases were older than female cases when they were detected. The proportion of Grade 2 Disability (G2D) among men (20.6%) was significantly higher than that among women (17.3%). The average period of delay in detection among male cases was similar with that among females cases.
Conclusions
Gender‐related differences existed among the leprosy cases detected from 2000 to 2015. Female patients were younger than male patients. The detection of leprosy in women was not later than in the case of men. The disability situation in men was more serious than in women.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The aim of this study was to determine the effects of diagnostic discordance with or without a thoracolumbar spine lateral view X-ray in patients with osteoporosis.
We randomly enrolled 368 women ...over 65 years old (74.3 ± 6.0 years) from Tianliao Township in 2009 (response rate: 75.7%). A diagnosis of osteoporosis was confirmed using one of these criteria: (1) a history of non-traumatic fracture, (2) vertebral fractures based on a thoracolumbar spine lateral view X-ray, or (3) a bone mineral density T-score ≤ -2.5 for the total hip, the femoral neck, the lumbar spine, or all 3 sites. The prevalence of osteoporosis in three groups was compared based on Model I (criteria 1+2) vs. Model II (criteria 1+3) vs. Model III (criteria 1+2+3). The role of thoracolumbar X-ray reflected by the diagnostic discordance of osteoporosis between Models II and III was evaluated.
The overall prevalence of osteoporosis was 78.3% (Model III, age-standardized 78.1%). The diagnostic discordance was 17.4% in the 368 participants. A logistic regression model showed that age was negatively associated with diagnostic discordance (odds ratio OR = 0.93, 95% confidence interval CI: 0.88-0.98, p < 0.05), but body mass index was positively associated (OR = 1.07, 95% CI: 1.00-1.15, p < 0.05).
A thoracolumbar spine lateral view X-ray should be added for women ≥ 65 years old or with a body mass index ≥ 25 kg/m2 to minimize the diagnostic discordance in osteoporosis, especially in highly endemic regions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We consider the problem of unsupervised domain adaptation for semantic segmentation by easing the domain shift between the source domain (synthetic data) and the target domain (real data) in this ...work. State-of-the-art approaches prove that performing semantic-level alignment is helpful in tackling the domain shift issue. Based on the observation that stuff categories usually share similar appearances across images of different domains while things (i.e. object instances) have much larger differences, we propose to improve the semantic-level alignment with different strategies for stuff regions and for things: 1) for the stuff categories, we generate feature representation for each class and conduct the alignment operation from the target domain to the source domain; 2) for the thing categories, we generate feature representation for each individual instance and encourage the instance in the target domain to align with the most similar one in the source domain. In this way, the individual differences within thing categories will also be considered to alleviate over-alignment. In addition to our proposed method, we further reveal the reason why the current adversarial loss is often unstable in minimizing the distribution discrepancy and show that our method can help ease this issue by minimizing the most similar stuff and instance features between the source and the target domains. We conduct extensive experiments in two unsupervised domain adaptation tasks, i.e. GTA5 → Cityscapes and SYNTHIA → Cityscapes, and achieve the new state-of-the-art segmentation accuracy.
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