bluuebunny/crossref_metadata_2025 huggingface dataset:
A new miocene–pliocene ichnotaxon for vermetid anchoring bioerosion structures
Authors: Verde Mariano , Castillo Carolina , Martín-González Esther , Cruzado-Caballero Penélope , Mayoral Eduardo , Santos Ana
Published: August 2022

A revision of Renichnus arcuatus Mayoral, 1987, the vermetid attachment etching trace fossil (fixichnia), is presented here with an emended diagnosis. Renichnus arcuatus should be used only for nested reniform depressions arranged in linear series or solitary ones. A new ichnotaxon, Santichnus mayorali ichnogen. et ichnosp. nov., is described to name a bioerosion structure that previous authors included under R. arcuatus. The new trace fossil comes from the Miocene–Pliocene deposits from Fuerteventura and Lanzarote, Canary Islands, and is characterized as a shallow canal, semicircular in cross-section that occurs on the surface of hard substrates. Santichnus mayorali follows a logarithmic spiral path that may depart in its outer whorl in a somewhat straight shaft that becomes recurved back toward the spiral. From an actualistic point of view, this new ichnotaxon is interpreted as the anchorage bioerosion structure of vermetid gastropods. Given the close relationship between the two ichnotaxa (Renichnus and Santichnus) that share vermetid gastropods as their tracemakers, it is proposed that they should be considered as compound trace fossils when they occur interconnected.
Social engagement: Hearing the experiences of disabled students in higher education in Ireland
Authors: Rath Vivian
Published: August 2022

Research on the experiences of disabled students in higher education in Ireland has focused primarily on barriers to their transition and academic experiences post entry. Their wider social engagement experiences have yet to be explored. Early and ongoing social engagement has been found to be particularly beneficial for non-traditional students leading to the creation of sense of belonging and greater student retention. There has been limited consideration of this area within Irish policy or research. As a disabled researcher with a human rights perspective. I adopted a qualitative framework which combined the transformative paradigm with the bio-ecological model. This approach enabled me to place the voice of the student at the center of the research whilst examining the system around them. The research upon which this article draws upon the findings of research carried out by a disabled researcher which brought together data from 65 participants, with representatives from 19 Higher Education Institutions (HEIs) across the Republic of Ireland using a four-phased, sequential, and concurrent qualitative data collection methodology. This paper focuses on the disabled undergraduate student cohort from this research (n = 23) and the theme of social engagement. The key findings under the theme of social engagement included, (i) Social engagement was highly valued and recognized as being vital to the formation of connections that resulted in a sense of belonging. (ii) The majority of disabled students reported being socially engaged, yet almost all reported barriers to their social engagement. (iii) A lack of disability awareness, inaccessible physical infrastructure, peer, and staff attitudes, negatively impact upon students’ sense of value, ability to maintain friendships, and develop a sense of belonging. (iv) There was little evidence of structures or a strategic approach to disabled students’ social engagement. These findings resonate with international research which demonstrated that disabled students face a range of systemic barriers to their social engagement in higher education. The implications of this research point to a failure of national and institutional policy to adequately consider the social engagement opportunities of disabled students within higher education.
Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH
Authors: Bonnet Laurianne , Alexandersson Ida , Baboota Ritesh K. , Kroon Tobias , Oscarsson Jan , Smith Ulf , Boucher Jeremie
Published: August 2022

Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines HepG2 and IHH with the senescence-inducing drugs nutlin-3a, doxorubicin and etoposide. The senescence-associated markers p16, p21, p53 and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis. Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of IR, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.
Optimization of the elimination of antibiotics by Lemna gibba and Azolla filiculoides using response surface methodology (RSM)
Authors: Maldonado Ingrid , Vega Quispe Anyela Pierina , Merma Chacca Donald , Zirena Vilca Franz
Published: August 2022

Antibiotic residues have been found in environmental samples, such as water, soil, and even food, and usually come from wastewater, presenting environmental and human health risks. This study aimed to improve the elimination of the antibiotics tetracycline (Tet) and chloramphenicol (Chlor) by modifying three factors: contact time (3–7 days), plant biomass (10–14 g), and antibiotic concentration (5–15 mg/L Tet and 10–20 mg/L Chlor). An approach that optimizes time and resources, response surface methodology (RSM), was applied with a Box–Behnken design (BBD) to two plant species (L. gibba and A. filiculoides), i.e., one experimental design was used for each species. Antibiotic residues in water and plant samples were analyzed by liquid chromatography. The optimal conditions for Tet removal were 6.04 d, 11.4 g, and 13.4 mg/L with Lemna and 6.3 d, 11.9 g, and 14.7 mg/L with Azolla; the optimal conditions for Chlor removal were 7.8 d, 13.6 g, and 10.2 mg/L with Lemna and 4.6 d, 12.3 g, and 8.7 mg/L with Azolla. The results showed that the removal efficiency of antibiotics increased depending on the species used, reaching a maximum of up to 100%. Tet was better removed than Chlor, reaching maximum removal values of 100% and 84% with Azolla and Lemna, respectively. Chlor removal reached 70% and 64% with Azolla and Lemna, respectively. The mean bioconcentration factors (BCFs) of Tet were 2.9% in Lemna and 4.9% in Azolla, and the BCFs for Chlor were 38.1% in Lemna and 37.8% in Azolla. Thus, in general, better results were obtained with Azolla. In summary, the results demonstrate that this design and the selected plants contribute to the removal of antibiotics, presenting a sustainable and recommended alternative for the treatment of wastewater contaminated with antibiotic residues.
How do chemical fertilizer reduction policies work? —Empirical evidence from rural china
Authors: Yang Yurong , Li Zhaoliang , Jin Minghao
Published: August 2022

China has issued a series of policies to regulate the usage of chemical fertilizer. Are these policies effective? If so, how do they work? To answer the above questions, this study empirically analyzed the effects of different types of policies (regulatory, incentive, and publicity policies), as well as their internal mechanisms and the moderating role of farmers’ risk attitudes, on the usage of chemical fertilizers in agricultural production. We found that the policies and their interactions had positive significant effects on the reduction of chemical fertilizer usage while the influences of their interaction variables were the most statistically significant, and the relationships between the policies and reduction were negatively regulated by the risk attitudes of the surveyed farmers. Furthermore, the policies encouraged chemical fertilizer reduction by improving the farmers’ income expectations while the farmers’ risk attitudes negatively regulated the intermediary effects of their income expectations. This study enhances the understanding of the influence of economic rationality on individual decision-making, as postulated in neoclassical economics, to a certain extent. The conclusions are of much practical significance to the substantial reduction of chemical fertilizers and the green transformation of agriculture in China.
Ecological networks and corridors development in urban areas: An example of Tabriz, Iran
Authors: Mahmoudzadeh Hassan , Masoudi Hassan , Jafari Firouz , Khorshiddoost Ali Mohammad , Abedini Asghar , Mosavi Amir
Published: August 2022

Landscape fragmentation and the elimination of urban green spaces are the results of human activities which put significant pressure on urban sustainability. The planning and developing of urban ecological networks and corridors as an effective approach is a response to rapid urbanization and fragmentation of natural areas. The Tabriz metropolitan as the fourth-largest city in Iran was selected as a case study that has grown rapidly over the past few decades. This study presents a practical approach and framework for assessing and enhancing ecological connectivity of landscape. The framework was developed based on the landscape metrics, graph theory, least-cost modeling, and geographic information system tools during three different periods (1984-2000-2020). The results using the values of landscape metrics such as CA, Edge Distance, Mean Patch Size, Mean Shape Index, large patch index, NP, Landscape shape index, and COHESION indicate that the urban landscape of Tabriz has been more fragmented over the past 3 decades and has lost its connectivity. To reduce the effects of fragmentation and enhance landscape connectivity in study area, we proposed a network of ecological corridors that passes through the core ecological patches. Our results also indicate that the core patches and the least-cost created corridors are mainly located in the suburbs of Tabriz and the central part of the city cannot be suitable for ecological development. Therefore, using the above-mentioned methods could be an effective approach to develop ecological networks and improve landscape connectivity that can encourage urban planners and managers to protect and develop green networks.
Integrated Analysis Reveals the Potential Significance of HDAC Family Genes in Lung Adenocarcinoma
Authors: Song Congkuan , Lin Weichen , Meng Heng , Li Ning , Geng Qing
Published: August 2022

Histone deacetylases comprise a family of 18 genes, and classical HDACs are a promising class of novel anticancer drug targets. However, to date, no systematic study has been comprehensive to reveal the potential significance of these 18 genes in lung adenocarcinoma (LUAD). Here, we used a systematic bioinformatics approach to comprehensively describe the biological characteristics of the HDACs in LUAD. Unsupervised consensus clustering was performed to identify LUAD molecular subtypes. The ssGSEA, CIBERSORT, MCP counter, and ESTIMATE algorithms were used to depict the tumor microenvironment (TME) landscape. The Cox proportional hazards model and LASSO regression analyses were used to construct the HDAC scoring system for evaluating the prognosis of individual tumors. In this study, three distinct HDAC-mediated molecular subtypes were determined, which were also related to different clinical outcomes and biological pathways. HDACsCluster-C subtype had lowest PD-L1/PD-1/CTLA4 expression and immune score. The constructed HDAC scoring system (HDACsScore) could be used as an independent predictor to assess patient prognosis and effectively identify patients with different prognosis. High- and low-HDACsScore groups presented distinct genetic features, immune infiltration, and biological processes. The high-HDACsScore group was more likely to benefit from immunotherapy, as well as from the application of common chemotherapeutic agents (cyclopamine, docetaxel, doxorubicin, gemcitabine, paclitaxel, and pyrimethamine). Overall, HDAC family genes play important roles in LUAD, and the three LUAD subtypes and the HDAC scoring system identified in this study would help enhance our perception of LUAD prognostic differences and provide important insights into the efficacy of immunotherapy and chemotherapy.
Circulating adipokine levels and preeclampsia: A bidirectional Mendelian randomization study
Authors: Chen Xiaoyan , Liu Zhaoming , Cui Jingen , Chen Xiaolan , Xiong Jing , Zhou Wei
Published: August 2022

Background: Several observational studies have demonstrated that significantly rising circulating adipokine levels are pervasive in preeclampsia or eclampsia disorder (or preeclampsia toxemia (PET)). However, it remains unclear whether this relationship is causal. In this study, we sought to elucidate the causal effects of circulating adipokine levels on PET.

Methods: Summary-level data and independent genetic variants strongly associated with common adipokine molecule (adiponectin, leptin, resistin, sOB-R, and PAI-1) levels were drawn from public genome-wide association study (GWASs). Additionally, the corresponding effects between instrumental variables and PET outcomes were acquired from the FinnGen consortium, including 4,743 cases and 136,325 controls of European ancestry. Subsequently, an inverse-variance weighted (IVW) approach was applied for the principal two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Various complementary sensitivity analyses were then carried out to determine the robustness of our models.

Results: The results of the IVW method did not reveal any causal relationship shared across genetically predisposed adipokine levels and PET risk (for adiponectin, OR = 0.86, 95% CI: 0.65–1.13, p = 0.274). Additionally, no significant associations were identified after taking into account five circulating adipokines in MVMR research. Complementary sensitivity analysis also supported no significant associations between them. In the reverse MR analysis, genetically predicted PET risk showed a suggestive association with elevating PAI-1 levels by the IVW method (Beta = 0.120, 95% CI: 0.014, 0.227, p = 0.026). Furthermore, there were no strong correlations between genetic liability to PET and other adipokine levels (p > 0.05).

Conclusion: Our MR study did not provide robust evidence supporting the causal role of common circulating adipokine levels in PET, whereas genetically predicted PET may instrumentally affect PAI-1 levels. These findings suggest that PAI-1 may be a useful biomarker for monitoring the diagnosis or therapy of PET rather than a therapeutic target for PET.
Clinical Utility of Medical Exome Sequencing: Expanded Carrier Screening for Patients Seeking Assisted Reproductive Technology in China
Authors: Tong Keya , He Wenbin , He Yao , Li Xiurong , Hu Liang , Hu Hao , Lu Guangxiu , Lin Ge , Dong Chang , Zhang Victor Wei , Du Juan , Liu Dongyun
Published: August 2022

Purpose: Expanded carrier screening (ECS) is an effective method to identify at-risk couples (ARCs) and avoid birth defects. This study aimed to reveal the carrier spectrum in the Chinese population and to delineate an expanded carrier gene panel suitable in China.

Methods: Medical exome sequencing (MES), including 4,158 disease-causing genes, was offered to couples at two reproductive centers. It was initially used as a diagnostic yield for potential patients and then used for ECS. Clinical information and ECS results were retrospectively collected.

Results: A total of 2,234 couples, representing 4,468 individuals, underwent MES. In total, 254 individuals showed genetic disease symptoms, and 56 of them were diagnosed with genetic diseases by MES. Overall, 94.5% of them were carriers of at least one disease-causing variant. The most prevalent genes were GJB2 for autosomal recessive disorders and G6PD for X-linked diseases. The ARC rate was 9.80%, and couples were inclined to undergo preimplantation genetic testing when diseases were classified as “profound” or “severe.”

Conclusion: This study provided insight to establish a suitable ECS gene panel for the Chinese population. Disease severity significantly influenced reproductive decision-making. The results highlighted the importance of conducting ECS for couples before undergoing assisted reproductive technology.
Predict potential miRNA-disease associations based on bounded nuclear norm regularization
Authors: Rao Yidong , Xie Minzhu , Wang Hao
Published: August 2022

Increasing evidences show that the abnormal microRNA (miRNA) expression is related to a variety of complex human diseases. However, the current biological experiments to determine miRNA-disease associations are time consuming and expensive. Therefore, computational models to predict potential miRNA-disease associations are in urgent need. Though many miRNA-disease association prediction methods have been proposed, there is still a room to improve the prediction accuracy. In this paper, we propose a matrix completion model with bounded nuclear norm regularization to predict potential miRNA-disease associations, which is called BNNRMDA. BNNRMDA at first constructs a heterogeneous miRNA-disease network integrating the information of miRNA self-similarity, disease self-similarity, and the known miRNA-disease associations, which is represented by an adjacent matrix. Then, it models the miRNA-disease prediction as a relaxed matrix completion with error tolerance, value boundary and nuclear norm minimization. Finally it implements the alternating direction method to solve the matrix completion problem. BNNRMDA makes full use of available information of miRNAs and diseases, and can deals with the data containing noise. Compared with four state-of-the-art methods, the experimental results show BNNRMDA achieved the best performance in five-fold cross-validation and leave-one-out cross-validation. The case studies on two complex human diseases showed that 47 of the top 50 prediction results of BNNRMDA have been verified in the latest HMDD database.
Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia
Authors: Loureiro Andrea V. , Moura-Neto Lauro I. , Martins Conceição S. , Silva Pedro I. M. , Lopes Matheus B.S. , Leitão Renata F. C. , Coelho-Aguiar Juliana M. , Moura-Neto Vivaldo , Warren Cirle A. , Costa Deiziane V.S. , Brito Gerly A. C.
Published: August 2022

Clostridioides difficile (C. difficile) produces toxins A (TcdA) and B (TcdB), both associated with intestinal damage and diarrhea. Pannexin-1 (Panx1) channels allows the passage of messenger molecules, such as adenosine triphosphate (ATP), which in turn activate the P2X7 receptors (P2X7R) that regulate inflammation and cell death in inflammatory bowel diseases. The aim of this study was to verify the effect of C. difficile infection (CDI) in the expression of Panx1 and P2X7R in intestinal tissues of mice, as well as their role in cell death and IL-6 expression induced by TcdA and TcdB in enteric glial cells (EGCs). Male C57BL/6 mice (8 weeks of age) were infected with C. difficile VPI10463, and the control group received only vehicle per gavage. After three days post-infection (p.i.), cecum and colon samples were collected to evaluate the expression of Panx1 by immunohistochemistry. In vitro, EGCs (PK060399egfr) were challenged with TcdA or TcdB, in the presence or absence of the Panx1 inhibitor (10Panx trifluoroacetate) or P2X7R antagonist (A438079), and Panx1 and P2X7R expression, caspase-3/7 activity and phosphatidylserine binding to annexin-V, as well as IL-6 expression were assessed. CDI increased the levels of Panx1 in cecum and colon of mice compared to the control group. Panx1 inhibitor decreased caspase-3/7 activity and phosphatidylserine-annexin-V binding, but not IL-6 gene expression in TcdA and TcdB-challenged EGCs. P2X7 receptor antagonist accentually reduced caspase-3/7 activity, phosphatidylserine-annexin-V binding, and IL-6 gene expression in TcdA and TcdB-challenged EGCs. In conclusion, Panx1 is increased during CDI and plays an important role in the effects of C. difficile toxins in EGCs, participating in cell death induced by both toxins by promoting caspase-3/7 activation via P2X7R, which is also involved in IL-6 expression induced by both toxins.
The differential expression and effects of Drosha on metamorphosis of Japanese flounder (paralichthys olivaceus)
Authors: Zhang Hongmei , Xu Zhaobin , Xu Junxiao , Wei Zhenlin , Shi Zhiyi
Published: August 2022

Drosha is critical for producing mature microRNAs (miRNAs) from their precursor molecules and small interfering RNAs (siRNAs). Although Drosha has been well characterized in most vertebrate species, identifying the Japanese flounder Drosha has remained elusive. In this study, we cloned the Japanese flounder Drosha gene, which has 4,122 nucleotides (nt), including a 5’-untranslated region (UTR) of 14 nt, a 3’-UTR of 230 nt, and a 3,879 nt open reading frame (ORF) encodes a 1,292 amino acid polypeptide. Then, we analyzed the conservation and phylogenetic evolution of Drosha in some species. Real-time quantitative PCR revealed that Drosha mRNA is highly expressed in the brain, and a lower amount of mRNA was also found in muscle than in other tissues. Drosha plays a vital role in controlling flounder development and metabolism, and its mRNA levels were relatively high at 36 dph (days post-hatching) in the period of metamorphosis and growth of the Japanese flounder. Drosha expression showed in advance with a peak at 23 dph following TH (thyroid hormone) treatment. To further investigate the role of Drosha in metamorphosis, we performed siRNA knockdown of Drosha in flounder embryonic cells (FEC) cells. The result shows that the Drosha-specific siRNA significantly down-regulated Drosha mRNA and miR-1,133,17,214,181a,181b levels, while primary miRNA (pri-miRNA) levels were not significantly different from negative control (NC). These results suggest that Drosha plays a vital role in Japanese flounder development and metamorphosis through processing to produce mature miRNAs, providing essential information for further studying of the part of the Drosha gene in the Japanese flounder development.
Barystatic and steric sea level variations in the Baltic Sea and implications of water exchange with the North Sea in the satellite era
Authors: Karimi Armin Agha , Ghobadi-Far Khosro , Passaro Marcello
Published: August 2022

Satellite altimetry, satellite gravimetry, and in-situ subsurface salinity and temperature profiles are used to investigate the total, barystatic, and steric sea level variations in the Baltic Sea, respectively. To estimate the steric sea level, the density variations are weighted in deeper layers to prevent overestimation of their contribution. We show that the sum of barystatic and steric components exhibits excellent cross correlation (0.9) with satellite altimetry sea level variations and also explains up to 84% of total signal variability from 2002 to 2019. Considering the dominance of barystatic sea level variations in the basin and the limitation of satellite gravimetry in resolving the mass change in water-land transition zones (known as the leakage problem), the mismatch is likely attributed to the inadequate accuracy of the barystatic datasets. The total sea level and its contributors are further decomposed into seasonal, interannual, and decadal temporal components. It is shown that despite its insignificant contributions to seasonal and interannual changes, the steric sea level plays an important role in decadal variations. Additionally, we show that the interannual variations of the barystatic sea level are governed by the North Atlantic Oscillation in the basin. The sea level variation in the North Sea is also examined to deduce the water exchange patterns on different time scales. A drop in the North Sea level can be seen from 2005 to 2011 which is followed by the Baltic Sea level with a ~3-year lag, implying the outflow from the Baltic Sea to the North Sea.
An overview on water masses in the China seas
Authors: Zhu Jia , Hu Jianyu , Zheng Quanan
Published: August 2022

This paper overviews progress in the research of water mass classification in the China seas, consisting of the Bohai Sea, the Yellow Sea, the East China Sea, the Taiwan Strait and the South China Sea. So far, oceanographers have achieved systematic research results in terms of the concept and definition, theory and method, characteristics and variation of water masses in the China seas. Here 3-D visualized diagrams are developed to illustrate spatial distributions of classified water masses in the China seas. Meanwhile, core values or ranges of temperature and salinity for individual water mass are integrated. Seasonal variations and formation mechanisms of water masses are briefly analyzed.
Engineered bone cement trigger bone defect regeneration
Authors: Xia Yuanliang , Wang Hengyi , Li Yuehong , Fu Changfeng
Published: August 2022

Bone defects, which can be caused by factors such as trauma, tumor, or osteomyelitis, are clinically common. They lessen the weight a bone is able to bear and cause severe pain to the patient. Although bone transplantation is the gold standard for treating bone defects, it is not suitable for all patients due to its poor availability, risk of spreading disease, and possibility of requiring a secondary surgery. Bone cement as a filler for bone defects can fill any shape of bone defect, and can quickly solidify when injected, providing mechanical strength sufficient for supporting the normal physiological activities of the bone. However, traditional bone cement lacks the ability to induce bone regeneration. Recently, various methods for enhancing the bone regeneration ability of bone cement have been developed, such as adding bone morphogenetic proteins, mesenchymal stem cells, and inorganic substances to bone cement. These methods not only ensure the original biological properties of the bone cement, but also improve the bone cement in terms of its mechanical strength and ability to induce bone regeneration. The aim of this review is to overview the process of bone regeneration, introduce improved bone cement formulations designed to promote bone regeneration, and discuss the clinical application of bone cement and its possibilities for future improvement.
Performance of presepsin and procalcitonin predicting culture-proven bacterial infection and 28-day mortality: A cross sectional study
Authors: Park Jiho , Yoon Ji Hyun , Ki Hyun Kyun , Ko Jae-Hoon , Moon Hee-Won
Published: August 2022

Presepsin is a highly specific biomarker for diagnosing bacterial infections, but its clinical usefulness is not well validated. A retrospective cross-sectional study was conducted. Among the patients suspected bacterial infection or fulfilled the criteria of systemic inflammatory response syndrome (SIRS) and patients who underwent blood culture, presepsin, procalcitonin (PCT), and C-reactive protein (CRP) at the same time were included. Receiver operating characteristic (ROC) curve analysis and logistic regression were used to compare performance of three biomarkers. A total of 757 patients were enrolled, including 256 patients (33.8%) with culture-proven bacterial infection and 109 patients (14.4%) with bacteremia. The 28-day mortality rate was 8.6%. ROC curve analysis revealed that the area under the curve (AUC) of PCT was higher than that of presepsin for both culture-proven bacterial infection (0.665 and 0.596, respectively; p = 0.003) and bacteremia (0.791 and 0.685; p < 0.001). In contrast, AUC of PCT for 28-day mortality was slower than presepsin (0.593 and 0.720; p = 0.002). In multivariable logistic regression analysis, PCT showed the highest ORs for culture-proven bacterial infection (OR 2.23, 95% CI 1.55–3.19; p < 0.001) and for bacteremia (OR 5.18, 95% CI 3.13–8.56; p < 0.001), while presepsin showed the highest OR for 28-day mortality (OR 3.31, 95% CI 1.67–6.54; p < 0.001). CRP did not show better performance than PCT or presepsin in any of the analyses. PCT showed the best performance predicting culture-proven bacterial infection and bacteremia, while presepsin would rather be useful as a prognostic marker.
A nomogram for predicting 10-year cancer specific survival in patients with pathological T3N0M0 rectal cancer
Authors: Liu Shuang , Yang Shanfei , Yu Haina , Luo Huilong , Chen Gong , Gao Yuanhong , Sun Rui , Xiao Weiwei
Published: August 2022

Background

The pathological T3N0M0 (pT3N0M0) rectal cancer is the earliest stage and has the best prognosis in the locally advanced rectal cancer, but the optimal treatment remains controversial. A reliable prognostic model is needed to discriminate the high-risk patients from the low-risk patients, and optimize adjuvant chemotherapy (ACT) treatment decisions by predicting the likelihood of ACT benefit for the target population.

Patients and methods

We gathered and analyzed 276 patients in Sun Yat-sen University Cancer Center from March 2005 to December 2011. All patients underwent total mesorectal excision (TME), without preoperative therapy, and were pathologically proven pT3N0M0 rectal cancer with negative circumferential resection margin (CRM). LASSO regression model was used for variable selection and risk factor prediction. Multivariable cox regression was used to develop the predicting model. Optimum cut-off values were determined using X-Tile plot analysis. The 10-fold cross-validation was adopted to validate the model. The performance of the nomogram was evaluated with its calibration, discrimination and clinical usefulness.

Results

A total of 188 patients (68.1%) had ACT and no patients had adjuvant radiotherapy. Age, monocyte percentage, carbohydrate antigen 19–9, lymph node dissection numbers and perineural invasion (PNI) were identified as significantly associated variables that could be combined for an accurate prediction risk of Cancer Specific Survival (CSS) for pT3N0M0 patients. The model adjusted for CSS showed good discrimination with a C-index of 0.723 (95% CI: 0.652–0.794). The calibration curves showed that the nomogram adjusted for CSS was able to predict 3-, 5-, and 10-year CSS accurately. The corresponding predicted probability was used to stratify high and low-risk patients (10-year CSS: 69.1% vs. 90.8%, HR = 3.815, 95%CI: 2.102–6.924, P < 0.0001). ACT improved overall survival (OS) in the low-risk patients (10-year OS: 91.9% vs. 83.3%, HR = 0.338, 95% CI: 0.135–0.848, P < 0.0001), while it did not exhibit a significant benefit in the high-risk patients.

Conclusion

The present study showed that age, monocyte percentage, carbohydrate antigen 19–9, lymph node dissection numbers and PNI were independent prognostic factors for pT3N0M0 rectal cancer patients. A nomogram based on these prognostic factors effectively predicts CSS in patients, which can be conveniently used in clinical practice. ACT may improve overall survival in the low-risk patients. But the benefit of ACT was not seen in the high-risk patients.
HupB, a nucleoid-associated protein, is critical for survival of Mycobacterium tuberculosis under host-mediated stresses and for enhanced tolerance to key first-line antibiotics
Authors: Singh Niti , Sharma Nishant , Singh Padam , Pandey Manitosh , Ilyas Mohd , Sisodiya Lovely , Choudhury Tejaswini , Gosain Tannu Priya , Singh Ramandeep , Atmakuri Krishnamohan
Published: August 2022

To survive and establish its niche, Mycobacterium tuberculosis (Mtb) engages in a steady battle against an array of host defenses and a barrage of antibiotics. Here, we demonstrate that Mtb employs HupB, a nucleoid-associated protein (NAP) as its key player to simultaneously battle and survive in these two stress-inducing fronts. Typically, NAPs are key to bacterial survival under a wide array of environmental or host-mediated stresses. Here, we report that for Mtb to survive under different macrophage-induced assaults including acidic pH, nutrient depletion, oxidative and nitrosative stresses, HupB presence is critical. As expected, the hupB knockout mutant is highly sensitive to these host-mediated stresses. Furthermore, Mtb aptly modulates HupB protein levels to overcome these stresses. We also report that HupB aids Mtb to gain tolerance to high levels of rifampicin (RIF) and isoniazid (INH) exposure. Loss of hupB makes Mtb highly susceptible to even short exposures to reduced amounts of RIF and INH. Overexpressing hupB in Mtb or complementing hupB in the hupB knockout mutant triggers enhanced survival of Mtb under these stresses. We also find that upon loss of hupB, Mtb significantly enhances the permeability of its cell wall by modulating the levels of several surface lipids including phthiocerol dimycocerosates (PDIMs), thus possibly influencing overall susceptibility to host-mediated stresses. Loss of hupB also downregulates efflux pump expression possibly influencing increased susceptibility to INH and RIF. Finally, we find that therapeutic targeting of HupB with SD1, a known small molecule inhibitor, significantly enhances Mtb susceptibility to INH and THP-1 macrophages and significantly reduces MIC to INH. Thus, our data strongly indicate that HupB is a highly promising therapeutic target especially for potential combinatorial shortened therapy with reduced INH and RIF doses.
Anti-quorum sensing evaluation of methyleugenol, the principal bioactive component, from the Melaleuca bracteata leaf oil
Authors: Wang Wenting , Lin Xiaojie , Yang Huixiang , Huang Xiaoqin , Pan Lei , Wu Shaohua , Yang Chao , Zhang Liaoyuan , Li Yongyu
Published: August 2022

Quorum sensing (QS) is a cell-to-cell communication in bacteria that couples gene expression through the accumulation of signaling molecules, which finally induce the production of several virulence factors and modulate bacterial behaviors. Plants have evolved an array of quorum sensing inhibitors (QSIs) to inhibit the pathogens, of which aromatic compounds are widely recognized. The essential oil of Melaleuca bracteata was found to exhibit anti-quorum sensing activity, and its principal bioactive component, methyleugenol (ME), had been isolated in our previous study. Here, ME interfered effectively with the QS-regulated processes of toxin secretion in Chomobacterium violaceum ATCC31532, resulting in strong inhibition of QS genes, cviR, cviI, vioA-E, hmsHNR, lasA-B, pilE1-3, and hcnABC, leading to impaired virulence, including violacein production, biofilm biomass, and swarming motility. The accumulation of the signal molecule (N-hexanoyl-DL-homoserine lactone, C6-HSL) in C. violaceum declined upon treatment with ME, suggesting an inhibition effect on the C6-HSL production, and the ME was also capable of degrading the C6-HSL in vitro assay. Molecular docking technique and the consumption change of exogenous C6-HSL in C. violaceum CV026 revealed the anti-QS mechanism of ME consisted of inhibition of C6-HSL production, potentially via interaction with CviR and/or CviI protein. Collectively, the isolated ME, the principal active components of M. bracteata EO, exhibited a wide range of inhibition processes targeting C. violaceum QS system, which supports the potential anti-pathogenic use of M. bracteata EO and ME for treatment of pathogen contamination caused by bacterial pathogens.
A microbial driver of clay mineral weathering and bioavailable Fe source under low-temperature conditions
Authors: Jung Jaewoo , Chung Hyun Young , Ko Youngtak , Moon Inkyeong , Suh Yeon Jee , Kim Kitae
Published: August 2022

Biotic and abiotic Fe(III) reduction of clay minerals (illite IMt-1) under low-temperature (0 and 4°C, pH 6) was studied to evaluate the effects of bioalteration on soil properties including clay structure and elemental composition. The extent of Fe reduction in bioreduced samples (∼3.8 % at 4°C and ∼3.1 % at 0°C) was lower than abiotic reduction (∼7.6 %) using dithionite as a strong reductant. However, variations in the illite crystallinity value of bioreduced samples (°Δ2θ = 0.580–0.625) were greater than those of abiotic reduced samples (°Δ2θ = 0.580–0.601), indicating that modification of crystal structure is unlikely to have occurred in abiotic reduction. Moreover, precipitation of secondary-phase minerals such as vivianite [Fe2+3(PO4)2⋅8H2O] and nano-sized biogenic silica were shown as evidence of reductive dissolution of Fe-bearing minerals that is observed only in a bioreduced setting. Our observation of a previously undescribed microbe–mineral interaction at low-temperature suggests a significant implication for the microbially mediated mineral alteration in Arctic permafrost, deep sea sediments, and glaciated systems resulting in the release of bioavailable Fe with an impact on low-temperature biogeochemical cycles.
Phenotypic response of yeast metabolic network to availability of proteinogenic amino acids
Authors: Simensen Vetle , Seif Yara , Almaas Eivind
Published: August 2022

Genome-scale metabolism can best be described as a highly interconnected network of biochemical reactions and metabolites. The flow of metabolites, i.e., flux, throughout these networks can be predicted and analyzed using approaches such as flux balance analysis (FBA). By knowing the network topology and employing only a few simple assumptions, FBA can efficiently predict metabolic functions at the genome scale as well as microbial phenotypes. The network topology is represented in the form of genome-scale metabolic models (GEMs), which provide a direct mapping between network structure and function via the enzyme-coding genes and corresponding metabolic capacity. Recently, the role of protein limitations in shaping metabolic phenotypes have been extensively studied following the reconstruction of enzyme-constrained GEMs. This framework has been shown to significantly improve the accuracy of predicting microbial phenotypes, and it has demonstrated that a global limitation in protein availability can prompt the ubiquitous metabolic strategy of overflow metabolism. Being one of the most abundant and differentially expressed proteome sectors, metabolic proteins constitute a major cellular demand on proteinogenic amino acids. However, little is known about the impact and sensitivity of amino acid availability with regards to genome-scale metabolism. Here, we explore these aspects by extending on the enzyme-constrained GEM framework by also accounting for the usage of amino acids in expressing the metabolic proteome. Including amino acids in an enzyme-constrained GEM of Saccharomyces cerevisiae, we demonstrate that the expanded model is capable of accurately reproducing experimental amino acid levels. We further show that the metabolic proteome exerts variable demands on amino acid supplies in a condition-dependent manner, suggesting that S. cerevisiae must have evolved to efficiently fine-tune the synthesis of amino acids for expressing its metabolic proteins in response to changes in the external environment. Finally, our results demonstrate how the metabolic network of S. cerevisiae is robust towards perturbations of individual amino acids, while simultaneously being highly sensitive when the relative amino acid availability is set to mimic a priori distributions of both yeast and non-yeast origins.
Defect detection on optoelectronical devices to assist decision making: A real industry 4.0 case study
Authors: Moustris George P. , Kouzas George , Fourakis Spyros , Fiotakis Georgios , Chondronasios Apostolos , Abu Ebayyeh Abd Al Rahman M. , Mousavi Alireza , Apostolou Kostas , Milenkovic Jovana , Chatzichristodoulou Zoi , Beckert Erik , Butet Jeremy , Blaser Stéphane , Landry Olivier , Müller Antoine
Published: August 2022

This paper presents an innovative approach, based on industry 4.0 concepts, for monitoring the life cycle of optoelectronical devices, by adopting image processing and deep learning techniques regarding defect detection. The proposed system comprises defect detection and categorization during the front-end part of the optoelectronic device production process, providing a two-stage approach; the first is the actual defect identification on individual components at the wafer level, while the second is the pre-classification of these components based on the recognized defects. The system provides two image-based defect detection pipelines. One using low resolution grating images of the wafer, and the other using high resolution surface scan images acquired with a microscope. To automate the entire process, a communication middleware called Higher Level Communication Middleware (HLCM) is used for orchestrating the information between the processing steps. At the last step of the process, a Decision Support System (DSS) collects all information, processes it and labels it with additional defect type categories, in order to provide recommendations to the optoelectronical engineer. The proposed solution has been implemented on a real industrial use-case in laser manufacturing. Analysis shows that chips validated through the proposed process have a probability to lase at a specific frequency six times higher than the fully rejected ones.
Repurposing food molecules as a potential BACE1 inhibitor for Alzheimer’s disease
Authors: Mukerjee Nobendu , Das Anubhab , Jawarkar Rahul D. , Maitra Swastika , Das Padmashree , Castrosanto Melvin A. , Paul Soumyadip , Samad Abdul , Zaki Magdi E. A. , Al-Hussain Sami A. , Masand Vijay H. , Hasan Mohammad Mehedi , Bukhari Syed Nasir Abbas , Perveen Asma , Alghamdi Badrah S. , Alexiou Athanasios , Kamal Mohammad Amjad , Dey Abhijit , Malik Sumira , Bakal Ravindra L. , Abuzenadah Adel Mohammad , Ghosh Arabinda , Md Ashraf Ghulam
Published: August 2022

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of β-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave β-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of β-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance (R2 = 0.82, Q2loo = 0.81). According to the QSAR study, the activity has a strong link with various atoms such as aromatic carbons and ring Sulfur, acceptor atoms, sp2-hybridized oxygen, etc. Following that, a database of 26,467 food compounds was primarily used for QSAR-based virtual screening accompanied by the application of the Lipinski rule of five; the elimination of duplicates, salts, and metal derivatives resulted in a truncated dataset of 8,453 molecules. The molecular descriptor was calculated and a well-validated 6-parametric version of the QSAR model was used to predict the bioactivity of the 8,453 food compounds. Following this, the food compounds whose predicted activity (pKi) was observed above 7.0 M were further docked into the BACE1 receptor which gave rise to the Identification of 4-(3,4-Dihydroxyphenyl)-2-hydroxy-1H-phenalen-1-one (PubChem I.D: 4468; Food I.D: FDB017657) as a hit molecule (Binding Affinity = −8.9 kcal/mol, pKi = 7.97 nM, Ki = 10.715 M). Furthermore, molecular dynamics simulation for 150 ns and molecular mechanics generalized born and surface area (MMGBSA) study aided in identifying structural motifs involved in interactions with the BACE1 enzyme. Molecular docking and QSAR yielded complementary and congruent results. The validated analyses can be used to improve a drug/lead candidate’s inhibitory efficacy against the BACE1. Thus, our approach is expected to widen the field of study of repurposing nutraceuticals into neuroprotective as well as anti-cancer and anti-viral therapeutic interventions.
Effect of exercise intervention on social distance in middle-aged and elderly patients with chronic low back pain
Authors: Weng Lin-Man , Wang Rui , Yang Qi-Hao , Chang Tian-Tian , Wu Cheng-Cheng , Li Wen-Long , Du Shu-Hao , Wang Yu-Chen , Wang Xue-Qiang
Published: August 2022

Background

Increased social distance is one of the manifestations of social impairment. Chronic low back pain (CLBP) is one of factors associated with increased social distance and social withdrawal. Exercise therapy is an effective means to social impairment. However, whether exercise could reduce social distance in patients with CLBP remains unknown. This study aimed to investigate the effect of exercise on social distance in middle-aged and elderly patients with CLBP.

Methods

The longitudinal intervention recruited 29 middle-aged and elderly patients with CLBP from various communities in Yangpu District, Shanghai, China. The participants received exercise intervention for 8 weeks. The assessments were conducted before and after the intervention, including social distance, pain intensity, unpleasantness of pain, Roland-Morris Questionnaire (RMDQ), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS). Intention to treat analysis was performed.

Results

After the 8-week exercise intervention, the social distance of patients with CLBP was shorter than that before intervention and showed significant difference (p < 0.05). The scores of pain intensity, unpleasantness of pain, RMDQ, SAS, and SDS also decreased and were significantly different between pre- and post-intervention (p < 0.05). In addition, the social distance, pain intensity, unpleasantness of pain, RMDQ, SAS, and SDS scores of the moderate CLBP group decreased more after the intervention compared with those of the mild CLBP group.

Conclusion

The 8-week exercise intervention cannot only shorten the social distance in middle-aged and elderly patients with CLBP but also relieve pain, disability, and negative emotions.