bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical performance of metagenomic next-generation sequencing for the rapid diagnosis of talaromycosis in HIV-infected patients
Authors: Mao Yuhuan , Shen Hui , Yang Caili , Jia Qunying , Li Jianying , Chen Yong , Hu Jinwei , Huang Weiliang
Published: October 2022

Background

Talaromycosis is an invasive endemic mycosis caused by the dimorphic fungus Talaromyces marneffei (T. marneffei, TM). It mainly affects immunodeficient patients, especially HIV-infected individuals, which causes significant morbidity and mortality. Culture-based diagnosis takes a long turnaround time with low sensitivity, leading to treatment delay. In this study, we aimed to evaluate the performance of Metagenomic Next-Generation Sequencing (mNGS) for the rapid diagnosis of talaromycosis in HIV-infected patients.

Methods

Retrospectively analysis was conducted in HIV-infected cases at Changsha First Hospital (China) from January 2021 to March 2022. Patients who underwent routine microbiological examination and mNGS testing in parallel were enrolled. The clinical final diagnosis was used as a reference standard, and cases were classified into the TM group (60 cases) and the non-TM group (148 cases). The clinical performances of mNGS were compared with culture and serum Galactomannan (GM). The mixed infections detected by mNGS were analyzed. The impact of mNGS detection on treatment was also investigated.

Results

The sensitivity of mNGS test reached 98.3% (95% CI, 89.8-99.9), which was significantly higher than culture (66.7% [95% CI, 53.2-77.9], P < 0.001) and serum GM (83.3% [95% CI, 71.0-91.2], P < 0.05). The specificity of 98.6% (95% CI, 94.7-99.7) was similar to culture (100.0% [95% CI, 96.8-100.0], P = 0.156), and superior to serum GM (91.9% [95% CI, 85.9-95.5], P < 0.05). In bronchoalveolar lavage fluid (BALF) samples, the positive rate of mNGS was 97.6%, which was significantly higher than culture (28.6%, P <0.001). mNGS has excellent performance in the identification of mixed infection in TM group patients. Cytomegalovirus, Epstein-Barr virus and Pneumocystis jirovecii were the most common concurrent pathogens. In summary, 60.0% (36/60) patients were added or adjusted to antimicrobial therapy after mNGS test.

Conclusion

mNGS is a powerful technique with high specificity and sensitivity for the rapid diagnosis of talaromycosis. mNGS of BALF samples may be a good option for early identification of T. marneffei in HIV-infected individuals with manifestations of infection. Moreover, mNGS shows excellent performance in mixed infection, which benefits timely treatment and potential mortality reduction.
To the farm, Mars, and beyond: Technologies for growing food in space, the future of long-duration space missions, and earth implications in English news media coverage
Authors: Shaw Ryland , Soma Tammara
Published: October 2022

The climate crisis, natural resource exploitation, and concerns around how to feed a growing world population have resulted in a growing chorus identifying the need for a Plan B. For some, this Plan B entails preparing for long-duration space missions and the development of human settlement on Mars. To plan for long-duration space missions, the development of food production technologies that can withstand extreme conditions such as poor soil, lack of gravity, and radiation are increasingly prioritized. These technologies may include genetic engineering, digital agriculture, 3D bioprinting, synthetically grown meat and more. Government and corporate proponents of long-duration space missions—NASA and SpaceX, among others—are actively funding agricultural research in space. They argue that the technologies developed for space will have positive implications beyond Mars—directly benefitting Earth and its inhabitants. This paper demonstrates that news reporting on the technology has been overall uncritical. Media narratives surrounding issues of food growth in space have not been studied. This study analyzes how English news media coverage (n= 170) from 67 publications report the feasibility of long-duration space missions, human settlements, and high-tech agricultural technologies. We provide a cross-section of the types of agricultural technologies being covered, the key organizations and actors in the field, and a critical analysis of media narratives. Using mixed methods content and discourse analysis, this study finds that the news media publications overwhelmingly portray long-duration space missions as both inevitable and a positive good for humanity. Without critically assessing the societal implications of food technologies for long-duration space missions vis-à-vis their benefits on Earth, we risk glossing over systemic and structural inequalities in the food system.
Nine receptors and binding proteins, four drugs, and one woman: Historical and personal perspectives
Authors: Novick Daniela
Published: October 2022

In the era of bioinformatics and high-throughput techniques, it is tempting to forget the advantage of an old yet efficient and straightforward technique, ligand affinity chromatography, in the search for unknown proteins. This type of separation is based on an interaction between the target analyte potentially present in a crude mixture of proteins and a ligand coupled covalently to a resin. This process allows thousands-fold purification in a single step, which is crucial when using an extremely rich source of naturally occurring proteins such as human urine or plasma. Before the completion of The Genome Project, this method facilitated the rapid and reliable cloning of the corresponding gene based on the partial amino acid sequence of the isolated protein. Upon completion of this project, a partial protein sequence was enough to retrieve its complete mRNA and, hence, its complete protein sequence. Ligand affinity chromatography is indispensable for the isolation of both expected and unexpected binding proteins found by serendipity. My approach of combining a rich source of human proteins (1,000-fold concentrated human urine) together with this highly specific isolation method yielded proteins from both groups. The expected proteins included the two receptors for TNF (TBPI and TBPII), type I and type II interferon receptors (IFNα/βR, IFN-γR), and IL-6 and LDL receptors. The unexpected group of proteins included IL-18 binding protein (IL-18BP), IL-32 binding protein (Proteinase 3), and heparanase binding protein, the resistin. The discovery of the type I IFN receptor was a “eureka” moment in my life since it put an end to a 35-year worldwide search for this receptor. Using chemical purification methods, the TBPII might have never been discovered. Years later, TBPII was translated into the blockbuster drug Enbrel®to treat mainly rheumatoid arthritis. IFN-beta was translated into the blockbuster drug Rebif®to treat the autoimmune disease multiple sclerosis. IL-18BP translated into the drug Tadekinig alfa™ and is in a phase III clinical study for inflammatory and autoimmune pathologies. It has saved the lives of children born with mutations (NLRC4, XIAP) and is an example of personalized medicine. COVID-19 and CAR-T cytokine storms are the recent targets of IL-18BP.
A machine learning-based virtual screening for natural compounds capable of inhibiting the HIV-1 integrase
Authors: Machado Lucas A. , Krempser Eduardo , Guimarães Ana Carolina Ramos
Published: October 2022

HIV-1 integrase is an essential enzyme for the HIV-1 replication cycle, and currently, integrase inhibitors are in the first line of treatment in many guidelines. Despite the discovery of new inhibitors, including a new class of molecules with different mechanisms of action, resistance is still a relevant problem, and adding new options to the therapeutic arsenal to fight viral resistance is a Sisyphean task. Because of the difficulty and cost of in vitro screenings, machine learning-driven ligand-based virtual screenings are an alternative that can not only cut costs but also use valuable information about active compounds with yet unknown mechanisms of action. In this work, we describe a thorough model exploration and hyperparameter tuning procedure in a dataset with class imbalance and show several models capable of distinguishing between compounds that are active or inactive against the HIV-1 integrase. The best of the models was then used to screen the natural product atlas for active compounds, resulting in a myriad of molecules that share features with known integrase inhibitors. Here we also explore the strengths and shortcomings of our models and discuss the use of the applicability domain to guide in vitro screenings and differentiate between the “predictable” and “unknown” regions of the chemical space.
The influence of work values of college students on entrepreneurial intention: The moderating role of psychological capital
Authors: Tian Lijun
Published: October 2022

Purpose

The aim of this study is to determine the influences of work values on entrepreneurial intention among college students. The moderating role of psychological capital was also examined.

Materials and methods

A total of 723 college students were investigated with work values questionnaire, entrepreneurial intention scale and positive psychological capital Questionnaire.

Results

Work values was significantly and positively correlated with entrepreneurial intention (r = 0.23, P < 0.001); Psychological capital was significantly and positively correlated with entrepreneurial intention (r = 0.33, P < 0.001); Psychological capital did not moderate the relationship between work values and entrepreneurial intention (β = 0.02, P > 0.05); Hope moderated the relationship between work values and unconditional entrepreneurial intention (β = 0.09, P < 0.05). The relationship between work values and unconditional entrepreneurial intention was stronger in the high hope group (simple slope = 0.21, p < 0.001) than in the low hope group (simple slope = 0.07, p < 0.001).

Conclusion

Hope moderates the relationship between work values and unconditional entrepreneurial intention. Improving the quality of hope can be used as an intervention to improve college students’ unconditional entrepreneurial intention.
The roles of mesenchymal stem cell-derived exosomes in diabetes mellitus and its related complications
Authors: Yang Mengmeng , Chen Jun , Chen Li
Published: October 2022

Diabetes mellitus is a type of metabolic disease characterized by hyperglycemia, primarily caused by defects in insulin secretion, insulin action, or both. Long-term chronic hyperglycemia can lead to diabetes-related complications, causing damage, dysfunction, and failure of different organs. However, traditional insulin and oral drug therapy can only treat the symptoms but not delay the progressive failure of pancreatic beta cells or prevent the emergence of diabetic complications. Mesenchymal stem cells have received extensive attention due to their strong immunoregulatory functions and regeneration effects. Mesenchymal stem cell-derived exosomes (MSC-Exos) have been proposed as a novel treatment for diabetic patients as they have demonstrated superior efficiency to mesenchymal stem cells. This review summarizes the therapeutic effects, mechanisms, challenges, and future prospects of MSC-Exos in treating diabetes mellitus and its related complications. This review supports the potential use of MSC-Exos in future regenerative medicine to overcome the current difficulties in clinical treatment, particularly in treating diabetes.
A combined signature of glycolysis and immune landscape predicts prognosis and therapeutic response in prostate cancer
Authors: Guo Tao , Wang Jian , Yan Shi , Meng Xiangyu , Zhang Xiaomin , Xu Shuang , Ren Shancheng , Huang Yuhua
Published: October 2022

Prostate cancer (PCa) is a common malignancy that poses a major threat to the health of men. Prostate-specific antigen (PSA) and its derivatives, as FDA-approved detection assays, are insufficient to serve as optimal markers for patient prognosis and clinical decision-making. It is widely acknowledged that aberrant glycolytic metabolism in PCa is related to tumor progression and acidifies the tumor microenvironment (TME). Considering the non-negligible impacts of glycolysis and immune functions on PCa, we developed a combined classifier in prostate cancer. The Glycolysis Score containing 19 genes and TME Score including three immune cells were created, using the univariate and multivariate Cox proportional hazards model, log-rank test, least absolute shrinkage and selection operator (LASSO) regression analysis and the bootstrap approach. Combining the glycolysis and immunological landscape, the Glycolysis-TME Classifier was then constructed. It was observed that the classifier was more accurate in predicting the prognosis of patients than the current biomarkers. Notably, there were significant differences in metabolic activity, signaling pathways, mutational landscape, immunotherapeutic response, and drug sensitivity among the Glycolysishigh/TMElow, Mixed group and Glycolysislow/TMEhigh identified by this classifier. Overall, due to the significant prognostic value and potential therapeutic guidance of the Glycolysis-TME Classifier, we anticipate that this classifier will be clinically beneficial in the management of patients with PCa.
Optical coherence tomography of the retina combined with color Doppler ultrasound of the tibial nerve in the diagnosis of diabetic peripheral neuropathy
Authors: Chen Weimiao , Wu Xiaohong , Li Shilin , Zhang Yan , Huang Yinqiong , Zhuang Yong , Bai Xuefeng , Chen Xiaoyu , Lin Xiahong
Published: October 2022

Objective

To investigate the value of the retinal nerve fiber layer (RNFL) thickness in the optic disc and the cross-sectional area (CSA) of lower limb nerves in the diagnosis of diabetic peripheral neuropathy (DPN) separately and in combination.

Methods

A total of 140 patients with type 2 diabetes were enrolled, including 51 patients with DPN (DPN group) and 89 patients without DPN (NDPN group). Clinical data and biochemical parameters were collected. Electromyography/evoked potential instrument was performed for nerve conduction study. Optical coherence tomography was performed to measure the RNFL thickness of the optic disc. Color Doppler ultrasound was performed to measure CSA of lower limb nerves.

Results

The RNFL thickness was lower and the CSA of the tibial nerve (TN) in the DPN group was larger than that in the NDPN group. The album/urine creatinine ratio, diabetic retinopathy, and CSA of TN at 3 cm were positively correlated with DPN. The RNFL thickness in the superior quadrant of the optic disc was negatively correlated with DPN. For RNFL thickness to diagnose DPN, the area under the curve (AUC) of the superior quadrant was the largest, which was 0.723 (95% confidence interval [CI]: 0.645–0.805), and the best cutoff value was 127.5 μm (70.5% sensitivity, 72.1% specificity). For CSA of TN to diagnose DPN, the AUC of the distance of 5 cm was the largest, which was 0.660 (95% CI: 0.575–0.739), and the best cutoff value was 13.50 mm2 (82.0% sensitivity, 41.6% specificity). For the combined index, the AUC was greater than that of the above two indicators, which was 0.755 (95% CI: 0.664–0.846), and the best cutoff value was 0.376 (64.3% sensitivity, 83.0% specificity).

Conclusions

Patients with DPN have a reduction of the RNFL thickness and an increase in the CSA of TN, and these two changes are related to DPN. The RNFL thickness of the optic disc and the CSA of TN can be used as diagnostic indicators of DPN, and the combination of the two indicators has a higher diagnostic value.
An efficient capuchin search algorithm for extracting the parameters of different PV cells/modules
Authors: Ali Hossam Hassan , Fathy Ahmed , Al-Dhaifallah Mujahed , Abdelaziz Almoataz Y. , Ebeed Mohamed
Published: October 2022

Constructing an equivalent circuit for the photovoltaic (PV) generating unit converging the real operation is a difficult process because of unavailability of some parameters. Many approaches have been conducted in this field; however, they have some problems in computational time and are stuck in local optima. Therefore, this study proposes a simple, robust, and efficient methodology-incorporated capuchin search algorithm (CapSA) to construct the equivalent circuit of the PV generating unit via identifying its parameters. The CapSA is selected as it is simple and requires less computational time in addition to exploration/exploitation balance that avoids local optima. The process is formulated as an optimization problem, which aims at minimizing the root mean square error (RMSE) between measured and simulated currents. A single-diode model (SDM), double-diode model (DDM), and three-diode model (TDM) of different PV cells and panels operating at either constant or variable weather conditions are constructed. A comparison to different programmed metaheuristic approaches is conducted. The best RMSE values obtained by the proposed CapSA are 2.27804E-04, 1.3808E-04, and 1.5182E-04 for SDM, DDM, and TDM of PVW 752 cell, respectively. For the KC200GT panel, the proposed approach achieved the best fitness values of 3.4440E-04, 1.5617E-03, and 6.6008E-03 at 25°C, 50°C, and 75°C, respectively. The obtained results confirmed the superiority and competence of the proposed CapSA in constructing a reliable equivalent circuit for the PV cell/panel.
Short-term day-ahead photovoltaic output forecasting using PCA-SFLA-GRNN algorithm
Authors: Gupta Ankur Kumar , Singh Rishi Kumar
Published: October 2022

The work of forecasting solar power is becoming more crucial with directives to regulate the quality of the power and increase the system’s reliability as photovoltaic (PV) sites are being integrated into the architecture of power systems at an increasing rate. This study proposes a metaheuristic model for short-term photovoltaic power forecasting that includes shuffled frog leaping algorithm (SFLA), principal component analysis (PCA), and generalized regression neural network (GRNN). In this model, GRNN is implemented to analyze the input parameters after the dimension reduction process, and its parameters get optimized with the help of the SFLA, which has the advantage of fast convergence speed as well as searching ability, whereas PCA techniques are implemented to diminish the dimension of meteorological conditions. This hybrid model achieves day-ahead short-term forecasting, as shown in an experimental case of a Bhadla Solar Park installed in Gujarat, India. The accuracy of the proposed model obtained a mean absolute error (nMAE) of 2.3325, and a root mean square error (RMSE) of 129.425. Similarly, the error in forecasting obtained by the proposed method results in nMAE = 2.977 and RMSE = 160.92. The output results obtained surpassed all other hybrid models used for comparison in this study.
Energy transport features of Oldroyd-B nanofluid flow over bidirectional stretching surface subject to Cattaneo–Christov heat and mass fluxes
Authors: Hussain Arafat , Iqbal Zahoor , Abdelmohimen Mostafa A. H. , Guedri Kamel , Tag-eldin Elsayed , Yassen Mansour F.
Published: October 2022

By considering the Cattaneo–Christov approach and Buongiorno’s model, the thermal transport model is formulated for the flow of Oldroyd-B nanofluid over a bidirectional stretching surface. The flow profile of Oldroyd-B nanofluid is examined for various physical parameters, and the effects of heat source/sink are also utilized to explore the thermal transport properties subject to thermal relaxation time. Governing mathematical models are developed on the basis of basic laws and presented in the form of Partial differential equations (PDEs). The governing partial differential equations are transformed into ordinary differential equations considering suitable dimensionless transformations. The homotopic method is applied to study the feature of heat and velocity components in fluid flow. The influence of each physical parameter over the thermal and concentration profile is displayed graphemically. It is noticed that thermal transport is decreasing with increment in thermal relaxation time. The mass transfer becomes weak with magnifying values of the stretching strength parameter. Moreover, the larger thermophoretic parameter regulates the heat transfer during fluid flow.
An energy efficient modified passive power filter for power quality enhancement in electric drives
Authors: Thentral T. M. Thamizh , Usha S. , Palanisamy R. , Geetha A. , Alkhudaydi Ahmed M. , Sharma Naveen Kumar , Bajaj Mohit , Ghoneim Sherif S. M. , Shouran Mokhtar , Kamel Salah
Published: October 2022

In most industrial applications, AC drives are used. These drives require power electronic modules to convert AC to DC and also DC to AC. The power modules used for power conversion consist of power semiconductor switches. There is distortion in the voltage and current obtained from the power modules due to non-linear behaviors of semiconductor switches. To reduce the distortion in the input current, inductors are used along with the line impedance. A high value of inductance is required to maintain the percentage of THD within limits set by the latest standards. Along with the increased size and cost, it also reduces the power factor and output DC voltage at higher loads. The use of a passive power filter (PPF) is the conventional method followed for the reduction of percentage THD and promotion of the power factor. PPFs comprise passive elements such as the resistor, inductor, and capacitor. These passive elements are connected at the point of common coupling (PCC) in shunt to compensate for the harmonics present in the input current. In this study, a modified multi-tuned passive filter is considered to reduce the source current harmonics. A bridge rectifier with resistive load, three-phase induction motor drive, and linear resistive–inductive load is connected at the point of common coupling to analyze the harmonics present in the source current, and also unbalanced created in one phase. To achieve proper selection of the resistance value for the passive filter, the class topper optimization technique is used. To validate the simulation results obtained for the multi-tuned passive filter, the hardware is implemented with a three-phase AC induction motor drive load, in which the speed of the motor is controlled with voltage by a frequency control algorithm using an FPGA controller; The 50% THD is reduced by using the fifth-order filter alone, 75% by combining the fifth- and seventh-order filters, 85% by combining the 5th-, 7th-, 11th-, 13th-, and higher-order filters, and 90% for varying loads. For single-phase AC induction motor load, THD % is reduced to 4%, and for three-phase AC induction motor drive, THD % is reduced to 10% with the same value of the filter.
The role of milk-derived exosomes in the treatment of diseases
Authors: Rashidi Mehdi , Bijari Salar , Khazaei Amir Hossein , Shojaei-Ghahrizjani Fereshteh , Rezakhani Leila
Published: October 2022

Exosomes (EXOs) are natural nanoparticles of endosome origin that are secreted by a variety of cells in the body. Exosomes have been found in bio-fluids such as urine, saliva, amniotic fluid, and ascites, among others. Milk is the only commercially available biological liquid containing EXOs. Proof that exosomes are essential for cell-to-cell communication is increasingly being reported. Studies have shown that they migrate from the cell of origin to various bioactive substances, including membrane receptors, proteins, mRNAs, microRNAs, and organelles, or they can stimulate target cells directly through interactions with receptors. Because of the presence of specific proteins, lipids, and RNAs, exosomes act in physiological and pathological conditions in vivo. Other salient features of EXOs include their long half-life in the body, no tumorigenesis, low immune response, good biocompatibility, ability to target cells through their surface biomarkers, and capacity to carry macromolecules. EXOs have been introduced to the scientific community as important, efficient, and attractive nanoparticles. They can be extracted from different sources and have the same characteristics as their parents. EXOs present in milk can be separated by size exclusion chromatography, density gradient centrifugation, or (ultra) centrifugation; however, the complex composition of milk that includes casein micelles and milk fat globules makes it necessary to take additional issues into consideration when employing the mentioned techniques with milk. As a rich source of EXOs, milk has unique properties that, in addition to its role as a carrier, promotes its use in treating diseases such as digestive problems, skin ulcers, and cancer, Moreover, EXOs derived from camel milk are reported to reduce the risk of oxidative stress and cancer. Milk-derived exosomes (MDEs) from yak milk improves gastrointestinal tract (GIT) development under hypoxic conditions. Furthermore, yak-MDEs have been suggested to be the best treatment for intestinal epithelial cells (IEC-6 cell line). Because of their availability as well as the non-invasiveness and cost-effectiveness of their preparation, isolates from mammals milk can be excellent resources for studies related to EXOs. These features also make it possible to exploit MDEs in clinical trials. The current study aimed to investigate the therapeutic applications of EXOs isolated from various milk sources.
CD146 is closely associated with the prognosis and molecular features of osteosarcoma: Guidance for personalized clinical treatment
Authors: Wang Jingkun , Wu Zhonghan , Zheng Meige , Yu Shuisheng , Zhang Xin , Xu XinZhong
Published: October 2022

Background: Osteosarcoma (OSA), a focus for orthopedic surgeons, always results in severe death due to metastasis. CD146 is severely expressed in several tumors, indicating its potential as a biomarker for OSA.

Method: Two OSA cohorts were enrolled in this study. A Therapeutically Applicable Research to Generate Effective Treatments-Osteosarcoma (TARGET-OS) cohort was used as a training cohort, and GSE21257 was used as the external validation cohort. The R package “limma” was used to discriminate the differentially expressed genes among CD146-high and CD146-low patients and was further annotated by the enriched signaling pathways. The R package MOVICS was used to evaluate immune infiltration and the response to chemotherapy and immunotherapy. All statistical analyses were performed by R version 4.0.2, and p < 0.05 was considered statistically significant.

Result: CD146 plays an important role in promoting the progression, invasion, and metastasis of several tumors. In the current study, we first revealed an integrative unfavorable prognosis in patients with tumors (p < 0.01, HR: 1.10, 95% CI: 1.07-1.14). CD146 is tightly correlated with m5C RNA methylation modification genes in OSA. Furthermore, we revealed that CD146 acts as an oncogene in OSA patients and is linked to poor prognosis in both the TARGET-OS cohort (p = 0.019, HR: 2.61, 95% CI: 1.171-5.834) and the GSE21257 cohort (p = 0.005, HR: 3.61, 95% CI: 1.474-8.855), with a total of 137 patients, regardless of whether they were adjusted for clinical pathological features. Highly-expressed CD146 impacts the signaling pathways of cytokine‒cytokine receptor interactions and is associated with the high infiltration of immunocytes. Moreover, patients with high CD146 expression were more likely to be sensitive to anti-PD-1 immunotherapy, while patients with low expression of CD146 were more likely to be sensitive to cisplatin and doxorubicin chemotherapy.

Conclusion: Overall, CD146 is an independent prognostic factor for OSA patients and can help doctors select clinical treatment strategies.
Caveolin-1 rs1997623 variant and adult metabolic syndrome—Assessing the association in three ethnic cohorts of Arabs, South Asians and South East Asians
Authors: Al Madhoun Ashraf , Hebbar Prashantha , Nizam Rasheeba , Haddad Dania , Melhem Motasem , Abu-Farha Mohamed , Thanaraj Thangavel Alphonse , Al-Mulla Fahd
Published: October 2022

Background: Animal and cell model studies have implicated CAV1 in the pathophysiology of metabolic disorders. Our previous studies demonstrated a potential association of CAV1 rs1997623 C/A variant with pediatric metabolic syndrome (MetS) in Arab children. In the present study, we evaluate whether the CAV1 variant associates with MetS Arab adults as well. The association signal is further examined for ancestry-specific variation by considering cohorts of other ethnicities.

Method: The CAV1 rs1997623 was genotyped in three cohorts of Arab (n = 479), South Asian (n = 660), and South East Asian (n = 362) ethnic adults from Kuwait. MetS status of the individuals was diagnosed using the IDF criteria (presence of central obesity and at least two abnormalities out of: elevated TG, low HDL, hypertension, or T2D). The quantitative measure of MetS was calculated as siMS = 2 × WC/Height + FBG/5.6 + TG/1.7 + SBP/130–HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous MetS traits were assessed using linear and logistic regression models adjusted for age and sex. In addition, empirical p-values (Pemp) were generated using max(T) permutation procedure based on 10,000 permutations.

Results: The CAV1 variant was significantly associated with MetS status (OR = 1.811 [1.25–2.61]; p-value = 0.0015; Pemp = 0.0013) and with siMS (Effect size = 0.206; p-value = 0.0035; Pemp = 0.0028) in the cohort of Arab individuals. The association was weak and insignificant in the South Asian and South East Asian cohorts (OR = 1.19 and 1.11; p-values = 0.25 and 0.67, respectively).

Conclusion: The reported association of CAV1 rs1997623 C/A with MetS in Arab pediatric population is now demonstrated in an adult Arab cohort as well. The weak association signal seen in the Asian cohorts lead us to propose a certain extent of ethnic-specificity in CAV1 rs1997623 association with MetS.
Light at the end of the tunnel: Clinical features and therapeutic prospects of KRAS mutant subtypes in non-small-cell lung cancer
Authors: Gao Liyuan , Shen Weizhang
Published: October 2022

Lung cancer is one of the most common causes of cancer-related deaths, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Kirsten rat sarcoma virus (KRAS), one of the three subtypes of the RAS family, is the most common oncogene involved in human cancers and encodes the key signaling proteins in tumors. Oncogenic KRAS mutations are considered the initiating factors in 30% of NSCLC cases, accounting for the largest proportion of NSCLC cases associated with driver mutations. Because effective inhibition of the related functions of KRAS with traditional small-molecule inhibitors is difficult, the KRAS protein is called an “undruggable target.” However, in recent years, the discovery of a common mutation in the KRAS gene, glycine 12 mutated to cysteine (G12C), has led to the design and synthesis of covalent inhibitors that offer novel strategies for effective targeting of KRAS. In this review, we have summarized the structure, function, and signal transduction pathways of KRAS and discussed the available treatment strategies and potential treatment prospects of KRAS mutation subtypes (especially G12C, G12V, and G12D) in NSCLC, thus providing a reference for selecting KRAS mutation subtypes for the treatment of NSCLC.
Fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis and intestinal inflammation in multiple sclerosis
Authors: Yadav Sudhir K. , Ito Naoko , Mindur John E. , Kumar Hetal , Youssef Mysra , Suresh Shradha , Kulkarni Ratuja , Rosario Yaritza , Balashov Konstantin E. , Dhib-Jalbut Suhayl , Ito Kouichi
Published: October 2022

Multiple Sclerosis (MS) has been reported to be associated with intestinal inflammation and gut dysbiosis. To elucidate the underlying biology of MS-linked gut inflammation, we investigated gut infiltration of immune cells during the development of spontaneous experimental autoimmune encephalomyelitis (EAE) in humanized transgenic (Tg) mice expressing HLA-DR2a and human T cell receptor (TCR) specific for myelin basic protein peptide (MBP87-99)/HLA-DR2a complexes. Strikingly, we noted the simultaneous development of EAE and colitis, suggesting a link between autoimmune diseases of the central nervous system (CNS) and intestinal inflammation. Examination of the colon in these mice revealed the infiltration of MBP-specific Th17 cells as well as recruitment of neutrophils. Furthermore, we observed that fecal Lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, was significantly elevated and predominantly produced by the gut-infiltrating neutrophils. We then extended our findings to MS patients and demonstrate that their fecal Lcn-2 levels are significantly elevated compared to healthy donors (HDs). The elevation of fecal Lcn-2 levels correlated with reduced bacterial diversity and increased levels of other intestinal inflammation markers including neutrophil elastase and calprotectin. Of interest, bacteria thought to be beneficial for inflammatory bowel disease (IBD) such as Anaerobutyricum, Blautia, and Roseburia, were reduced in fecal Lcn-2-high MS patients. We also observed a decreasing trend in serum acetate (a short-chain fatty acid) levels in MS Lcn-2-high patients compared to HDs. Furthermore, a decrease in the relative abundance of Blautia massiliensis was significantly associated with a reduction of acetate in the serum of MS patients. This study suggests that gut infiltration of Th17 cells and recruitment of neutrophils are associated with the development of gut dysbiosis and intestinal inflammation, and that fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis in multiple sclerosis.
Proteomic and phosphorylated proteomic landscape of injured lung in juvenile septic rats with therapeutic application of umbilical cord mesenchymal stem cells
Authors: Wang Hongwu , Luo Junlin , Li Aijia , Su Xing , Fang Chuiqin , Xie Lichun , Wu Yi , Wen Feiqiu , Liu Yufeng , Wang Tianyou , Zhong Yong , Ma Lian
Published: October 2022

Acute lung injury (ALI) is the most common complication of sepsis. Intravenous injection of HUMSCs can regulate the level of circulating endothelial cytokines and alleviate lung injury in juvenile septic rats. In this study, we performed proteomic and phosphorylated proteomic analysis of lung tissue of juvenile septic rats after Human Umbilical Cord Mesenchymal Stem Cells (HUMSCs) intervention for the first time, and screened the potential proteins and pathways of HUMSCs for therapeutic effect. The 4D proteome quantitative technique was used to quantitatively analyze the lung tissues of septic rats 24 hours (3 biological samples) and 24 hours after HUMSCs intervention (3 biological samples). A total of 213 proteins were identified as differentially expressed proteins, and 971 phosphorylation sites changed significantly. Based on the public database, we analyzed the functional enrichment of these proteins and phosphorylated proteins. In addition, Tenascin-C may be the key differential protein and ECM receptor interaction pathway may be the main signal pathway by using various algorithms to analyze the protein-protein interaction network. Phosphorylation analysis showed that tight junction pathway was closely related to immune inflammatory reaction, and EGFR interacted most, which may be the key differential phosphorylated protein. Finally, 123 conserved motifs of serine phosphorylation site (pS) and 17 conserved motifs of threonine (pT) phosphorylation sites were identified by motif analysis of phosphorylation sites. Results from proteomics and phosphorylated proteomics, the potential new therapeutic targets of HUMSCs in alleviating lung injury in juvenile septic rats were revealed.
Modulating the microenvironment during FVIII uptake influences the nature of FVIII-peptides presented by antigen-presenting cells
Authors: Lubich Christian , Steinitz Katharina Nora , Hoelbl Brigitte , Prenninger Thomas , van Helden Pauline Maria , Weiller Markus , Reipert Birgit Maria
Published: October 2022

Background and aims

Hemophilia A is a severe bleeding disorder caused by the deficiency of functionally active coagulation factor VIII (FVIII). The induction of neutralizing anti-drug antibodies is a major complication in the treatment of hemophilia A patients with FVIII replacement therapies. Why some patients develop neutralizing antibodies (FVIII inhibitors) while others do not is not well understood. Previous studies indicated that the induction of FVIII inhibitors requires cognate interactions between FVIII-specific B cells and FVIII-specific CD4+ T cells in germinal center reactions. In this study, we investigated the FVIII peptide repertoire presented by antigen-presenting cells (APCs) under different microenvironment conditions that are expected to alter the uptake of FVIII by APCs. The aim of this study was to better understand the association between different microenvironment conditions during FVIII uptake and the FVIII peptide patterns presented by APCs.

Methods

We used a FVIII-specific CD4+ T cell hybridoma library derived from humanized HLA-DRB1*1501 (human MHC class II) hemophilic mice that were treated with human FVIII. APCs obtained from the same mouse strain were preincubated with FVIII under different conditions which are expected to alter the uptake of FVIII by APCs. Subsequently, these preincubated APCs were used to stimulate the FVIII-specific CD4+ T cell hybridoma library. Stimulation of peptide-specific CD4+ T-cell hybridoma clones was assessed by analyzing the IL-2 release into cell culture supernatants.

Results

The results of this study indicate that the specific microenvironment conditions during FVIII uptake by APCs determine the peptide specificities of subsequently activated FVIII-specific CD4+ T cell hybridoma clones. Incubation of APCs with FVIII complexed with von Willebrand Factor, FVIII activated by thrombin or FVIII combined with a blockade of receptors on APCs previously associated with FVIII uptake and clearance, resulted in distinct peptide repertoires of subsequently activated hybridoma clones.

Conclusion

Based on our data we conclude that the specific microenvironment during FVIII uptake by APCs determines the FVIII peptide repertoire presented on MHC class II expressed by APCs and the peptide specificity of subsequently activated FVIII-specific CD4+ T cell hybridoma clones.
Mining of immunological and prognostic-related biomarker for cervical cancer based on immune cell signatures
Authors: Wang Nana , Nanding Abiyasi , Jia Xiaocan , Wang Yuping , Yang Chaojun , Fan Jingwen , Dong Ani , Zheng Guowei , Ma Jiaxin , Shi Xuezhong , Yang Yongli
Published: October 2022

Background

Immunotherapy has changed the therapeutic landscape of cervical cancer (CC), but has durable anti-tumor activity only in a subset of patients. This study aims to comprehensively analyze the tumor immune microenvironment (TIME) of CC and to mine biomarkers related to immunotherapy and prognosis.

Methods

The Cancer Genome Atlas (TCGA) data was utilized to identify heterogeneous immune subtypes based on survival-related immune cell signatures (ICSs). ICSs prognostic model was constructed by Cox regression analyses, and immunohistochemistry was conducted to verify the gene with the largest weight coefficient in the model. Meanwhile, the tumor immune infiltration landscape was comprehensively characterized by ESTIMATE, CIBERSORT and MCPcounter algorithms. In addition, we also analyzed the differences in immunotherapy-related biomarkers between high and low-risk groups. IMvigor210 and two gynecologic tumor cohorts were used to validate the reliability and scalability of the Risk score.

Results

A total of 291 TCGA-CC samples were divided into two ICSs clusters with significant differences in immune infiltration landscape and prognosis. ICSs prognostic model was constructed based on eight immune-related genes (IRGs), which showed higher overall survival (OS) rate in the low-risk group (P< 0.001). In the total population, time-dependent receiver operating characteristic (ROC) curves displayed area under the curve (AUC) of 0.870, 0.785 and 0.774 at 1-, 3- and 5-years. Immunohistochemical results showed that the expression of the oncogene (FKBP10) was negatively correlated with the degree of differentiation and positively correlated with tumor stage, while the expression of tumor suppressor genes (S1PR4) was the opposite. In addition, the low-risk group had more favorable immune activation phenotype and higher enrichment of immunotherapy-related biomarkers. The Imvigor210 and two gynecologic tumor cohorts validated a better survival advantage and immune efficacy in the low-risk group.

Conclusion

This study comprehensively assessed the TIME of CC and constructed an ICSs prognostic model, which provides an effective tool for predicting patient’s prognosis and accurate immunotherapy.
Non-heme iron overload impairs monocyte to macrophage differentiation via mitochondrial oxidative stress
Authors: Cui Yue , Gutierrez Saray , Ariai Sheller , Öberg Lisa , Thörn Kristofer , Gehrmann Ulf , Cloonan Suzanne M. , Naessens Thomas , Olsson Henric
Published: October 2022

Iron is a key element for systemic oxygen delivery and cellular energy metabolism. Thus regulation of systemic and local iron metabolism is key for maintaining energy homeostasis. Significant changes in iron levels due to malnutrition or hemorrhage, have been associated with several diseases such as hemochromatosis, liver cirrhosis and COPD. Macrophages are key cells in regulating iron levels in tissues as they sequester excess iron. How iron overload affects macrophage differentiation and function remains a subject of debate. Here we used an in vitro model of monocyte-to-macrophage differentiation to study the effect of iron overload on macrophage function. We found that providing excess iron as soluble ferric ammonium citrate (FAC) rather than as heme-iron complexes derived from stressed red blood cells (sRBC) interferes with macrophage differentiation and phagocytosis. Impaired macrophage differentiation coincided with increased expression of oxidative stress-related genes. Addition of FAC also led to increased levels of cellular and mitochondrial reactive oxygen species (ROS) and interfered with mitochondrial function and ATP generation. The effects of iron overload were reproduced by the mitochondrial ROS-inducer rotenone while treatment with the ROS-scavenger N-Acetylcysteine partially reversed FAC-induced effects. Finally, we found that iron-induced oxidative stress interfered with upregulation of M-CSFR and MAFB, two crucial determinants of macrophage differentiation and function. In summary, our findings suggest that high levels of non-heme iron interfere with macrophage differentiation by inducing mitochondrial oxidative stress. These findings might be important to consider in the context of diseases like chronic obstructive pulmonary disease (COPD) where both iron overload and defective macrophage function have been suggested to play a role in disease pathogenesis.
Low density Plasmodium infections and G6PD deficiency among malaria suspected febrile individuals in Ethiopia
Authors: Abagero Beka R. , Kepple Daniel , Pestana Kareen , Witherspoon Logan , Biruksew Abdissa , Adanew Abinet , Baharu Fetiya , Hansel Shantoy , Lopez Karen , Janies Daniel A. , Lo Eugenia , Yewhalaw Delenasaw
Published: October 2022

The identification and management of low parasitemia infections have become increasingly challenging for malaria control and elimination. Submicroscopic Plasmodium infections and G6PD deficiency among febrile patients require more sensitive diagnostic methods to improve detection and careful treatment regime of these infections. In Ethiopia, information on the low density submicroscopic malarial infections and frequency of G6PD deficiency (G6PDd) is scarce. In this study, 297 malaria suspected febrile patient samples were collected from health facilities of Bonga town in southwestern Ethiopia. The positivity rates of Plasmodium infection were determined by microscopy and quantitative PCR. G6PD activity level was determined by careSTART™ G6PD biosensor and the frequency of three common variants: G6PD*A (A376G), G6PD*A− (G202A) and Mediterranean (C563T) were investigated. G6PD gene sequencing was performed to detect mutations in exons 2–11 for both G6PD normal and deficient samples based on the phenotypic assay. More than twice Plasmodium infected samples was detected by qPCR (52/297; 17.4%) than microscopy (21/297; 7.0%). About 31 (10%) of the infections were submicroscopic. Bednet usage and age had a significant association with Plasmodium infection. Of the 271 participants who were tested for G6PD phenotype, 19 (7.0%) had low G6PD level. No mutations were observed in A376G, G202A, and C563T in the G6PDd samples, but three novel non-synonymous mutations in exon 2 including a C to T transition at position ChrX:6504 (Arg to Thr), G to T at ChrX:6369 (Ser to IIe), and G to C at ChrX:6664 (Gln to His) were detected. A high number of submicroscopic Plasmodium infections observed in this study pose a challenge for accurate and timely diagnosis, which could hinder malaria control efforts. G6PD deficiency in malaria patients pose danger when treating patients with primaquine. The three novel mutations detected in exon 2 of the G6PD gene merit further investigation on the hemolytic risk when exposed to oxidative antimalarials, their prevalence, and clinical significance.
Multi-method biophysical analysis in discovery, identification, and in-depth characterization of surface‐active compounds
Authors: Zompra Aikaterini A. , Chasapi Styliani A. , Twigg Matthew S. , Salek Karina , Anestopoulos Ioannis , Galanis Alex , Pappa Aglaia , Gutierrez Tony , Banat Ibrahim M. , Marchant Roger , Euston Stephen R. , Panayiotidis Mihalis I. , Spyroulias Georgios A.
Published: October 2022

Synthetic surfactants are used in several industries, including manufacturing, pharmaceutical and cosmetic’s, food and feed, agriculture, petroleum and environmental remediation for their ability to adsorb to fluid and solid-water interfaces. However, their widespread use and their synthetic preparation through environmentally unfavorable processes counterbalances the value of this class of reagents. This fact has stimulated new efforts to exploit natural sources of surfactants, such as new classes of bacterial systems or manipulation of existing biological systems, that may produce, through an environmentally friendly process, new biodegradable surfactants and emulsifiers of high commercial value. A downside of microbial production of biobased chemicals such as these types of chemicals, is that their fermentation often yields crude materials consisting of several bioproducts with complex physical and chemical properties. Extraction, identification, and efficient characterization of biosurfactants from a crude mixture of biomolecules requires carefully designed, and detailed analytical processes using state-of-the-art methods. The purpose of this review article is to present the current state-of-the-art and future outlook on the various multidisciplinary biophysical methods applied in the discovery, extraction identification, and in-depth characterization of microbially-produced surface‐active compounds.
An “Eddy β-Spiral” mechanism for vertical velocity dipole patterns of isolated oceanic mesoscale eddies
Authors: Hou Yinglin , Jin Fei-Fei , Gao Shan , Zhao Jun , Liu Kai , Qu Tangdong , Wang Fan
Published: October 2022

Oceanic eddies accompanied by a significant vertical velocity (w) are known to be of great importance for the vertical transport of various climatically, biologically or biogeochemically relevant properties. Using quasi-geostrophic w-thinking to extend the classic “β-spiral” w-theory for gyre circulations to isolated and nearly symmetric oceanic mesoscale eddies, we propose that their w motion will be dominated by a strong east-west dipole pattern with deep ocean penetrations. Contrasting numerical simulations of idealized isolated eddies together with w-equation diagnostics confirm that the w-dipole is indeed dominated by the “eddy β-spiral” mechanism in the β-plane simulation, whereas this w-dipole expectedly disappears in the f-plane simulation. Analyses of relatively isolated warm and cold eddy examples show good agreement with the proposed mechanism. Our studies further clarify eddy vertical motions, have implications for ocean mixing and vertical transport, and inspire further studies.