bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioproduction of Linalool From Paper Mill Waste
Authors: Rinaldi Mauro A. , Tait Shirley , Toogood Helen S. , Scrutton Nigel S.
Published: June 2022

A key challenge in chemicals biomanufacturing is the maintenance of stable, highly productive microbial strains to enable cost-effective fermentation at scale. A “cookie-cutter” approach to microbial engineering is often used to optimize host stability and productivity. This can involve identifying potential limitations in strain characteristics followed by attempts to systematically optimize production strains by targeted engineering. Such targeted approaches however do not always lead to the desired traits. Here, we demonstrate both ‘hit and miss’ outcomes of targeted approaches in attempts to generate a stable Escherichia coli strain for the bioproduction of the monoterpenoid linalool, a fragrance molecule of industrial interest. First, we stabilized linalool production strains by eliminating repetitive sequences responsible for excision of pathway components in plasmid constructs that encode the pathway for linalool production. These optimized pathway constructs were then integrated within the genome of E. coli in three parts to eliminate a need for antibiotics to maintain linalool production. Additional strategies were also employed including: reduction in cytotoxicity of linalool by adaptive laboratory evolution and modification or homologous gene replacement of key bottleneck enzymes GPPS/LinS. Our study highlights that a major factor influencing linalool titres in E. coli is the stability of the genetic construct against excision or similar recombination events. Other factors, such as decreasing linalool cytotoxicity and changing pathway genes, did not lead to improvements in the stability or titres obtained. With the objective of reducing fermentation costs at scale, the use of minimal base medium containing paper mill wastewater secondary paper fiber as sole carbon source was also investigated. This involved simultaneous saccharification and fermentation using either supplemental cellulase blends or by co-expressing secretable cellulases in E. coli containing the stabilized linalool production pathway. Combined, this study has demonstrated a stable method for linalool production using an abundant and low-cost feedstock and improved production strains, providing an important proof-of-concept for chemicals production from paper mill waste streams. For scaled production, optimization will be required, using more holistic approaches that involve further rounds of microbial engineering and fermentation process development.
Effects of 4 Weeks of High-Definition Transcranial Direct Stimulation and Foot Core Exercise on Foot Sensorimotor Function and Postural Control
Authors: Xiao Songlin , Wang Baofeng , Zhang Xini , Zhou Junhong , Fu Weijie
Published: June 2022

Objective: This study aimed to examine the effects of 4 weeks of high-definition transcranial direct current stimulation (HD-tDCS) and foot core exercise (FCE) on foot sensorimotor function (i.e., toe flexor strength and passive ankle kinesthesia) and postural control.

Methods: In total, 36 participants were randomly assigned into three groups as follows: HD-tDCS, FCE, and the control group. A total of 12 training sessions were performed over 4 weeks (i.e., three sessions per week) in the laboratory. The HD-tDCS group received 20-min HD-tDCS with a current density of 2 mA, and the FCE group completed short foot exercise, towel curls, toe spread and squeeze, and balance board training. Participants in the control group just maintained the activities what they usually did and did not receive any interventions. Foot muscle strength, passive ankle kinesthesia, and postural control were assessed at baseline and post-intervention.

Results: HD-tDCS induced a greater decrease in the percentage changes in the passive kinesthesia thresholds of ankle inversion (p < 0.001) and eversion (p = 0.013) than the control group. Compared with the control group, a significant increase in the percentage change in the metatarsophalangeal joint flexor strength was found in the HD-tDCS group (p = 0.008) and the FCE group (p = 0.027), and a significant increase in the percentage change in toe flexor strength was observed in the FCE group (p = 0.015). Moreover, FCE induced a greater reduction in the percent changes in the medial–lateral average center of gravity sway velocity in one-leg standing with eyes open (p = 0.033) and the anteroposterior average center of gravity sway velocity in one-leg standing with eyes closed (p < 0.001) than control.

Conclusion: This study demonstrated that 4 weeks of HD-tDCS and FCE induced distinct benefits on foot sensorimotor function and the standing postural control performance in healthy young adults. HD-tDCS could improve the metatarsophalangeal joint flexor strength and the passive kinesthesia thresholds of ankle inversion and eversion. Meanwhile, FCE could also enhance foot muscle strength and enhance postural control performance in one-leg standing.
Review on the Application of Hyperspectral Imaging Technology of the Exposed Cortex in Cerebral Surgery
Authors: Wu Yue , Xu Zhongyuan , Yang Wenjian , Ning Zhiqiang , Dong Hao
Published: June 2022

The study of brain science is vital to human health. The application of hyperspectral imaging in biomedical fields has grown dramatically in recent years due to their unique optical imaging method and multidimensional information acquisition. Hyperspectral imaging technology can acquire two-dimensional spatial information and one-dimensional spectral information of biological samples simultaneously, covering the ultraviolet, visible and infrared spectral ranges with high spectral resolution, which can provide diagnostic information about the physiological, morphological and biochemical components of tissues and organs. This technology also presents finer spectral features for brain imaging studies, and further provides more auxiliary information for cerebral disease research. This paper reviews the recent advance of hyperspectral imaging in cerebral diagnosis. Firstly, the experimental setup, image acquisition and pre-processing, and analysis methods of hyperspectral technology were introduced. Secondly, the latest research progress and applications of hyperspectral imaging in brain tissue metabolism, hemodynamics, and brain cancer diagnosis in recent years were summarized briefly. Finally, the limitations of the application of hyperspectral imaging in cerebral disease diagnosis field were analyzed, and the future development direction was proposed.
Tuning the Properties of Protein-Based Polymers Using High-Performance Orthogonal Translation Systems for the Incorporation of Aromatic Non-Canonical Amino Acids
Authors: Gueta Osher , Sheinenzon Ortal , Azulay Rotem , Shalit Hadas , Strugach Daniela S. , Hadar Dagan , Gelkop Sigal , Milo Anat , Amiram Miriam
Published: June 2022

The incorporation of non-canonical amino acids (ncAAs) using engineered aminoacyl-tRNA synthetases (aaRSs) has emerged as a powerful methodology to expand the chemical repertoire of proteins. However, the low efficiencies of typical aaRS variants limit the incorporation of ncAAs to only one or a few sites within a protein chain, hindering the design of protein-based polymers (PBPs) in which multi-site ncAA incorporation can be used to impart new properties and functions. Here, we determined the substrate specificities of 11 recently developed high-performance aaRS variants and identified those that enable an efficient multi-site incorporation of 15 different aromatic ncAAs. We used these aaRS variants to produce libraries of two temperature-responsive PBPs—elastin- and resilin-like polypeptides (ELPs and RLPs, respectively)—that bear multiple instances of each ncAA. We show that incorporating such aromatic ncAAs into the protein structure of ELPs and RLPs can affect their temperature responsiveness, secondary structure, and self-assembly propensity, yielding new and diverse families of ELPs and RLPs, each from a single DNA template. Finally, using a molecular model, we demonstrate that the temperature-responsive behavior of RLPs is strongly affected by both the hydrophobicity and the size of the unnatural aromatic side-chain. The ability to efficiently incorporate multiple instances of diverse ncAAs alongside the 20 natural amino acids can help to elucidate the effect of ncAA incorporation on these and many other PBPs, with the aim of designing additional precise and chemically diverse polymers with new or improved properties.
A Hybrid Particle-Flow CFD Modeling Approach in Truncated Hepatic Arterial Trees for Liver Radioembolization: A Patient-specific Case Study
Authors: Bomberna Tim , Vermijs Saar , Lejoly Maryse , Verslype Chris , Bonne Lawrence , Maleux Geert , Debbaut Charlotte
Published: June 2022

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. At its intermediate, unresectable stage, HCC is typically treated by local injection of embolizing microspheres in the hepatic arteries to selectively damage tumor tissue. Interestingly, computational fluid dynamics (CFD) has been applied increasingly to elucidate the impact of clinically variable parameters, such as injection location, on the downstream particle distribution. This study aims to reduce the computational cost of such CFD approaches by introducing a novel truncation algorithm to simplify hepatic arterial trees, and a hybrid particle-flow modeling approach which only models particles in the first few bifurcations. A patient-specific hepatic arterial geometry was pruned at three different levels, resulting in three trees: Geometry 1 (48 outlets), Geometry 2 (38 outlets), and Geometry 3 (17 outlets). In each geometry, 1 planar injection and 3 catheter injections (each with different tip locations) were performed. For the truncated geometries, it was assumed that, downstream of the truncated outlets, particles distributed themselves proportional to the blood flow. This allowed to compare the particle distribution in all 48 “outlets” for each geometry. For the planar injections, the median difference in outlet-specific particle distribution between Geometry 1 and 3 was 0.21%; while the median difference between outlet-specific flow and particle distribution in Geometry 1 was 0.40%. Comparing catheter injections, the maximum median difference in particle distribution between Geometry 1 and 3 was 0.24%, while the maximum median difference between particle and flow distribution was 0.62%. The results suggest that the hepatic arterial tree might be reliably truncated to estimate the particle distribution in the full-complexity tree. In the resulting hybrid particle-flow model, explicit particle modeling was only deemed necessary in the first few bifurcations of the arterial tree. Interestingly, using flow distribution as a surrogate for particle distribution in the entire tree was considerably less accurate than using the hybrid model, although the difference was much higher for catheter injections than for planar injections. Future work should focus on replicating and experimentally validating these results in more patient-specific geometries.
Construction and Optimization of the de novo Biosynthesis Pathway of Mogrol in Saccharomyces Cerevisiae
Authors: Wang Siyu , Xu Xianhao , Lv Xueqin , Liu Yanfeng , Li Jianghua , Du Guocheng , Liu Long
Published: June 2022

Mogrol plays important roles in antihyperglycemic and antilipidemic through activating the AMP-activated protein kinase pathway. Although the synthesis pathway of mogrol in Siraitia grosvenorii has been clarified, few studies have focused on improving mogrol production. This study employed a modular engineerin g strategy to improve mogrol production in a yeast chassis cell. First, a de novo synthesis pathway of mogrol in Saccharomyces cerevisiae was constructed. Then, the metabolic flux of each synthetic module in mogrol metabolism was systematically optimized, including the enhancement of the precursor supply, inhibition of the sterol synthesis pathway using the Clustered Regularly Interspaced Short Palindromic Repeats Interference system (CRISPRi), and optimization of the expression and reduction system of P450 enzymes. Finally, the mogrol titer was increased to 9.1 μg/L, which was 455-fold higher than that of the original strain. The yeast strains engineered in this work can serve as the basis for creating an alternative way for mogrol production in place of extraction from S. grosvenorii.
Transcriptome-Wide m6A Methylome and m6A-Modified Gene Analysis in Asthma
Authors: Sun Deyang , Cai Xiaolu , Shen Fenglin , Fan Liming , Yang Huan , Zheng Suqun , Zhou Linshui , Chen Ke , Wang Zhen
Published: June 2022

N6-methyladenosine (m6A) modification is one of the most prevalent RNA modification forms and is an important posttranscriptional mechanism for regulating genes. In previous research, we found that m6A regulator–mediated RNA methylation modification was involved in asthma; however, the specific modified genes are not clear. In this study, we systematically evaluated the transcriptome-wide m6A methylome and m6A-modified genes in asthma. Here, we performed two high-throughput sequencing methods, methylated RNA immunoprecipitation sequencing (MeRIP-seq), and RNA sequencing (RNA-seq) to identify key genes with m6A modification in asthma. Through difference analysis, we found that 416 methylation peaks were significantly upregulated and 152 methylation peaks were significantly downregulated, and it was mainly distributed in 3′ UTR. Furthermore, compared with the control group, there were 2,505 significantly upregulated genes and 4,715 significantly downregulated genes in the asthma group. Next, through a combined analysis of transcriptome and differential peaks, 14 differentially expressed genes related to RNA methylation modification were screened. Finally, through 87 health controls and 411 asthma cases from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) program, we verified three m6A-modified key genes (BCL11A, MATK, and CD300A) and found that they were mainly distributed in exons and enriched in 3' UTR. Our findings suggested that intervening in m6A-modified genes may provide a new idea for the treatment of asthma.
Generation of a H9 Clonal Cell Line With Inducible Expression of NUP98-KDM5A Fusion Gene in the AAVS1 Safe Harbor Locus
Authors: Domingo-Reinés Joan , Martínez-Navajas Gonzalo , Montes Rosa , Lamolda Mar , Simón Iris , Castaño Julio , Ríos-Pelegrina Rosa , Lopez-Hidalgo Javier Luis , García del Moral Raimundo , Marchal Juan A. , Real Pedro J. , Ramos-Mejía Verónica
Published: June 2022

Pediatric acute myeloid leukemia (AML) is a rare and heterogeneous disease that remains the major cause of mortality in children with leukemia. To improve the outcome of pediatric AML we need to gain knowledge on the biological bases of this disease. NUP98-KDM5A (NK5A) fusion protein is present in a particular subgroup of young pediatric patients with poor outcome. We report the generation and characterization of human Embryonic Stem Cell (hESC) clonal lines with inducible expression of NK5A. Temporal control of NK5A expression during hematopoietic differentiation from hESC will be critical for elucidating its participation during the leukemogenic process.
Unconventional Secretion of Plant Extracellular Vesicles and Their Benefits to Human Health: A Mini Review
Authors: Farley Joshua T. , Eldahshoury Mahmoud K. , de Marcos Lousa Carine
Published: June 2022

Mechanisms devoted to the secretion of proteins via extracellular vesicles (EVs) have been found in mammals, yeasts, and plants. Since they transport a number of leader-less proteins to the plasma membrane or the extracellular space, EVs are considered part of Unconventional protein secretion (UPS) routes. UPS involving EVs are a relatively new field in plants. Aside from their role in plant physiology and immunity, plant extracts containing EVs have also been shown to be beneficial for human health. Therefore, exploring the use of plant EVs in biomedicine and their potential as drug delivery tools is an exciting avenue. Here we give a summary of the state of knowledge on plant EVs, their crosstalk with mammalian systems and potential research routes that could lead to practical applications in therapeutic drug delivery.
The Key Role of RNA Modification in Breast Cancer
Authors: Liu Yang , Zhu Tong , Jiang Yi , Bu Jiawen , Zhu Xudong , Gu Xi
Published: June 2022

The modulation of the function and expression of epigenetic regulators of RNA modification has gradually become the hotspot of cancer research. Studies have shown that alteration of epigenetic modifications can promote the development and metastasis of breast cancer. This review highlights the progress in characterization of the link between RNA modification and the prognosis, carcinogenesis and treatment of breast cancer, which may provide a new theoretical basis for development of effective strategies for monitoring of breast cancer based on epigenetics.
The Role of Tissue-Resident Macrophages in the Development and Treatment of Inflammatory Bowel Disease
Authors: Ma Shengjie , Zhang Jiaxin , Liu Heshi , Li Shuang , Wang Quan
Published: June 2022

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a refractory disease with many immune abnormalities and pathologies in the gastrointestinal tract. Because macrophages can distinguish innocuous antigens from potential pathogens to maintain mucosa barrier functions, they are essential cells in the intestinal immune system. With numerous numbers in the intestinal tract, tissue-resident macrophages have a signiﬁcant effect on the constant regeneration of intestinal epithelial cells and maintaining the immune homeostasis of the intestinal mucosa. They also have a significant influence on IBD through regulating pro-(M1) or anti-inﬂammatory (M2) phenotype polarization according to different environmental cues. The disequilibrium of the phenotypes and functions of macrophages, disturbed by intracellular or extracellular stimuli, influences the progression of disease. Further investigation of macrophages’ role in the progression of IBD will facilitate deciphering the pathogenesis of disease and exploring novel targets to develop novel medications. In this review, we shed light on the origin and maintenance of intestinal macrophages, as well as the role of macrophages in the occurrence and development of IBD. In addition, we summarize the interaction between gut microbiota and intestinal macrophages, and the role of the macrophage-derived exosome. Furthermore, we discuss the molecular and cellular mechanisms participating in the polarization and functions of gut macrophages, the potential targeted strategies, and current clinical trials for IBD.
An Isogenic Collection of Pluripotent Stem Cell Lines With Elevated α-Synuclein Expression Validated for Neural Induction and Cortical Neuron Differentiation
Authors: Natalwala Ammar , Behbehani Ranya , Yapom Ratsuda , Kunath Tilo
Published: June 2022

α-Synuclein (αSyn) is a small, disordered protein that becomes aggregated in Lewy body diseases, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Human induced pluripotent stem cells (hiPSCs) potentially provide a tractable disease model to monitor early molecular changes associated with PD/DLB. We and others have previously derived hiPSC lines from patients with duplication and triplication of the SNCA gene, encoding for αSyn. It is now recognised that to perform meaningful disease modelling with these hiPSC lines, it is critical to generate isogenic control cell lines that lack the disease causing mutations. In order to complement the existing and emerging hiPSC models for PD/DLB, we have generated an allelic series of αSyn over-expressing hESC lines on the same isogenic background. An unresolved question is whether pluripotent stem cell lines, with elevated levels of αSyn, can undergo efficient differentiation into dopaminergic and cortical neurons to model PD and DLB, respectively. We took advantage of our isogenic collection of hESC lines to determine if increased expression of αSyn affects neural induction and neuronal differentiation. Clonal hESC lines with significantly different levels of αSyn expression proliferated normally and maintained expression of pluripotent markers, such as OCT4. All cell lines efficiently produced PAX6+ neuroectoderm and there was no correlation between αSyn expression and neural induction efficiency. Finally, global transcriptomic analysis of cortical differentiation of hESC lines with low or high levels of αSyn expression demonstrated robust and similar induction of cortical neuronal expression profiles. Gene expression differences observed were unrelated to neural induction and neuronal differentiation. We conclude that elevated expression of αSyn in human pluripotent stem cells does not adversely affect their neuronal differentiation potential and that collections of isogenic cell lines with differing levels of αSyn expression are valid and suitable models to investigate synucleinopathies.
Tumor-Stroma Interaction in PDAC as a New Approach for Liquid Biopsy and its Potential Clinical Implications
Authors: Götze Julian , Nitschke Christine , Uzunoglu Faik G. , Pantel Klaus , Sinn Marianne , Wikman Harriet
Published: June 2022

The extremely poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) has remained unchanged for decades. As a hallmark of PDAC histology, the distinct desmoplastic response in the tumor microenvironment is considered a key factor exerting pro- and antitumor effects. Increasing emphasis has been placed on cancer-associated fibroblasts (CAFs), whose heterogeneity and functional diversity is reflected in the numerous subtypes. The myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs) and antigen presenting CAFs (apCAFs) are functionally divergent CAF subtypes with tumor promoting as well as repressing effects. Precise knowledge of the underlying interactions is the basis for a variety of treatment approaches, which are subsumed under the term antistromal therapy. Clinical implementation is still pending due to the lack of benefit—as well as paradoxical preclinical findings. While the prominent significance of CAFs in the immediate environment of the tumor is becoming clear, less is known about the circulating (c)CAFs. cCAFs are of particular interest as they seem not only to be potential new liquid biopsy biomarkers but also to support the survival of circulating tumor cells (CTC) in the bloodstream. In PDAC, CTCs correlate with an unfavorable outcome and can also be employed to monitor treatment response, but the current clinical relevance is limited. In this review, we discuss CTCs, cCAFs, secretomes that include EVs or fragments of collagen turnover as liquid biopsy biomarkers, and clinical approaches to target tumor stroma in PDAC.
Capillary Microreactor for Initial Screening of Three Amine-Based Solvents for CO2 Absorption, Desorption, and Foaming
Authors: Ashok Anchu , Ballout Jaafar , Benamor Abdelbaki , Al-Rawashdeh Ma’moun
Published: June 2022

Microreactor is a very attractive laboratory device for screening conditions and solvents in an efficient, safe and fast manner. Most reported work on microreactors for CO2 capturing deals with absorption and mass transfer performance with a limited number of studies on solvent regeneration. For the first time, foaming, which is a major operational challenge of CO2 capturing is being studied in combination with absorption and desorption in a capillary microreactor setup. To demonstrate the setup capabilities, three known amine-based solvents (MEA, MDEA, and AMP) were selected for the screening and evaluation studies. MEA had the highest CO2 absorption efficiency while MDEA had the lowest one. CO2 absorption efficiency increased with temperature, liquid flow rate, and amine concentration as per the literature. During the absorption work, the Taylor flow regime was maintained at the reactor inlet. CO2 desorption of loaded amine solutions was investigated at different concentrations and temperatures up to 85°C. MDEA solution had the highest desorption efficiency, followed by AMP and the least desorption efficiency was that of MEA. Foaming experimental results showed that MEA had a larger foaming region compared to AMP. However, more foaming happened with AMP at higher gas and liquid flow rates. A plug flow mathematical reactor model was developed to simulate the MEA-CO2 system. The model captured well the performance and trends of the studied system, however the absolute prediction deviated due to uncertainties in the used physical properties and mass transfer correlation. Selecting a solvent for chemical absorption depends on many more factors than these three studied parameters. Still, microreactor proves a valuable tool to generate experimental results under different conditions, with the least amount of consumables (less than 1 L solvents were used), in a fast manner, combined with a knowledge insight because of the uniqueness of the Taylor flow regime.
Minor Tobacco Alkaloids as Biomarkers to Distinguish Combusted Tobacco Use From Electronic Nicotine Delivery Systems Use. Two New Analytical Methods
Authors: Jacob Peyton , Chan Lawrence , Cheung Polly , Bello Kristina , Yu Lisa , StHelen Gideon , Benowitz Neal L.
Published: June 2022

Biomarkers for the use of electronic nicotine delivery systems (ENDS) are desirable for studies of the health effects of electronic cigarettes and related devices. However, the aerosols inhaled from these devices do not contain substances that are unique to this class of products, i.e., substances that are not present in cigarette smoke or those that do not have common environmental or dietary sources. Consequently, identifying selective biomarkers for ENDS use remains a challenge. If co-use of conventional tobacco products can be definitively ruled out, then nicotine and its metabolites are suitable for assessing exposure. Self-reports from questionnaires are often used to obtain information on product use. But self-reports may not always be accurate, and are not amenable to obtaining quantitative information on exposure. An alternative approach is to use selective biomarkers for conventional tobacco products to definitively rule out their use. In this article, we describe two new LC-MS/MS methods for the minor tobacco alkaloids anabasine, anatabine, nicotelline, anatalline, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a tobacco-specific nitrosamine metabolite, all biomarkers that are selective for the use of conventional tobacco products. Applications of these biomarkers in studies of ENDS use and dual use of ENDS and conventional tobacco products are also discussed.
Unnatural Amino Acid: 4-Aminopyrazolonyl Amino Acid Comprising Tri-Peptides Forms Organogel With Co-Solvent (EtOAc:Hexane)
Authors: Bollu Amarnath , Giri Prajnanandan , Dalabehera Nihar Ranjan , Asmi Asmita Rani , Sharma Nagendra K.
Published: June 2022

Ampyrone is an amino-functionalized heterocyclic pyrazolone derivative that possesses therapeutic values such as analgesic, anti-inflammatory, and antipyretics. The chemical structure of ampyrone exhibits excellent hydrogen bonding sites and is considered as the potential scaffold of supramolecular self-assembly. Recently, this molecule has been derived into unnatural amino acids such as aminopyrazolone amino acid and its peptides. This report describes that one of its amino acids, O-alkylated ampyrone, containing hybrid (α/β) peptides forms organogel after sonication at 50–55°C with 0.7–0.9% (w/v) in ethyl acetate: hexane (1:3). The formation/morphology of such organogels is studied by nuclear magnetic resonance Fourier-transform infrared (FT-IR), circular dichroism (CD), scanning electron microscope (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (Powder-XRD), and thermogravimetric analysis (TGA). Energy-minimized conformation of APA-peptides reveals the possibility of intermolecular hydrogen bonding. Hence, APA-peptides are promising peptidomimetics for the organogel-peptides.
Demonstration of a New Characterization Method for Weak Measurement
Authors: Xu Yang , Shi Lixuan , Zhou Chongqi , Li Zhangyan , Guan Tian , Xing Xinhui , Liu Le , He Yonghong
Published: June 2022

In this work, the difference between the weak measurement method and the weak value amplification process and the classical measurement process is thoroughly discussed, and the transition conditions of the weak value enhancement are obtained. A transition mode of the weak measurement and the classical measurement is proposed for the first time, and a better fitting model of the measurement results is found by performing a systematic analysis. On top of that, the importance of the new fitting method for the application of the weak measurement system is verified during the industrial production of organic molecular -nucleic acid, protein, polysaccharide-hydrolysis or synthesis. At the same time, a variety of spectral characterization methods are proposed and the advantages and disadvantages of the different characterization methods are analyzed through carrying out experiments. Consequently, the wide implementation of weak measurement-based detection technology is attained.
Design of Ni(OH)2/M-MMT Nanocomposite With Higher Charge Transport as a High Capacity Supercapacitor
Authors: Xu G. M. , Wang M. , Bao H. L. , Fang P. F. , Zeng Y. H. , Du L. , Wang X. L.
Published: June 2022

Nano-petal nickel hydroxide was prepared on multilayered modified montmorillonite (M-MMT) using one-step hydrothermal method for the first time. This nano-petal multilayered nanostructure dominated the ion diffusion path to be shorted and the higher charge transport ability, which caused the higher specific capacitance. The results showed that in the three-electrode system, the specific capacitance of the nanocomposite with 4% M-MMT reached 1068 F/g at 1 A/g and the capacity retention rate was 70.2% after 1,000 cycles at 10 A/g, which was much higher than that of pure Ni(OH)2 (824 F/g at 1 A/g), indicating that the Ni(OH)2/M-MMT nanocomposite would be a new type of environmentally friendly energy storage supercapacitor.
Spaceflight Analogue Culture Enhances the Host-Pathogen Interaction Between Salmonella and a 3-D Biomimetic Intestinal Co-Culture Model
Authors: Barrila Jennifer , Yang Jiseon , Franco Meléndez Karla P. , Yang Shanshan , Buss Kristina , Davis Trenton J. , Aronow Bruce J. , Bean Heather D. , Davis Richard R. , Forsyth Rebecca J. , Ott C. Mark , Gangaraju Sandhya , Kang Bianca Y. , Hanratty Brian , Nydam Seth D. , Nauman Eric A. , Kong Wei , Steel Jason , Nickerson Cheryl A.
Published: June 2022

Physical forces associated with spaceflight and spaceflight analogue culture regulate a wide range of physiological responses by both bacterial and mammalian cells that can impact infection. However, our mechanistic understanding of how these environments regulate host-pathogen interactions in humans is poorly understood. Using a spaceflight analogue low fluid shear culture system, we investigated the effect of Low Shear Modeled Microgravity (LSMMG) culture on the colonization of Salmonella Typhimurium in a 3-D biomimetic model of human colonic epithelium containing macrophages. RNA-seq profiling of stationary phase wild type and Δhfq mutant bacteria alone indicated that LSMMG culture induced global changes in gene expression in both strains and that the RNA binding protein Hfq played a significant role in regulating the transcriptional response of the pathogen to LSMMG culture. However, a core set of genes important for adhesion, invasion, and motility were commonly induced in both strains. LSMMG culture enhanced the colonization (adherence, invasion and intracellular survival) of Salmonella in this advanced model of intestinal epithelium using a mechanism that was independent of Hfq. Although S. Typhimurium Δhfq mutants are normally defective for invasion when grown as conventional shaking cultures, LSMMG conditions unexpectedly enabled high levels of colonization by an isogenic Δhfq mutant. In response to infection with either the wild type or mutant, host cells upregulated transcripts involved in inflammation, tissue remodeling, and wound healing during intracellular survival. Interestingly, infection by the Δhfq mutant led to fewer transcriptional differences between LSMMG- and control-infected host cells relative to infection with the wild type strain. This is the first study to investigate the effect of LSMMG culture on the interaction between S. Typhimurium and a 3-D model of human intestinal tissue. These findings advance our understanding of how physical forces can impact the early stages of human enteric salmonellosis.
The Cross-Species Immunity During Acute Babesia Co-Infection in Mice
Authors: Zafar Iqra , Galon Eloiza May , Kondoh Daisuke , Efstratiou Artemis , Li Jixu , Ji Shengwei , Liu Mingming , Li Yongchang , Hasegawa Yae , Zhou Jinlin , Xuan Xuenan
Published: June 2022

Babesiosis causes high morbidity and mortality in immunocompromised individuals. An earlier study suggested that lethal Babesia rodhaini infection in murine can be evaded by Babesia microti primary infection via activated macrophage-based immune response during the chronic stage of infection. However, whether the same immune dynamics occur during acute B. microti co-infection is not known. Hence, we used the mouse model to investigate the host immunity during simultaneous acute disease caused by two Babesia species of different pathogenicity. Results showed that B. microti primary infection attenuated parasitemia and conferred immunity in challenge-infected mice as early as day 4 post-primary infection. Likewise, acute Babesia co-infection undermined the splenic immune response, characterized by the significant decrease in splenic B and T cells leading to the reduction in antibody levels and decline in humoral immunity. Interestingly, increased macrophage and natural killer splenic cell populations were observed, depicting their subtle role in the protection. Pro-inflammatory cytokines (i.e. IFN-γ, TNF-α) were downregulated, while the anti-inflammatory cytokine IL-10 was upregulated in mouse sera during the acute phase of Babesia co-infection. Herein, the major cytokines implicated in the lethality caused by B. rodhaini infection were IFN- γ and IL-10. Surprisingly, significant differences in the levels of serum IFN- γ and IL-10 between co-infected survival groups (day 4 and 6 challenge) indicated that even a two-day delay in challenge infection was crucial for the resulting pathology. Additionally, oxidative stress in the form of reactive oxygen species contributed to the severity of pathology during acute babesiosis. Histopathological examination of the spleen showed that the erosion of the marginal zone was more pronounced during B. rodhaini infection, while the loss of cellularity of the marginal zone was less evident during co-infection. Future research warrants investigation of the roles of various immune cell subtypes in the mechanism involved in the protection of Babesia co-infected hosts.
Using a Large Climate Ensemble to Assess the Frequency and Intensity of Future Extreme Climate Events in Southern Africa
Authors: Thomas Timothy S. , Schlosser C. Adam , Strzepek Kenneth , Robertson Richard D. , Arndt Channing
Published: June 2022

This paper uses 7,200 smoothed climate change projections for each of the four emissions scenarios, together with inter-annual variation provided by detrended historical climate data to investigate changes in growing season (wettest 3 months) weather patterns from the 2020s to the 2060s for ten countries of Southern Africa. The analysis is done in 8,888 quarter-degree pixels by month. Temperature unequivocally rises in the region, but it rises relatively less along the coasts, particularly on the eastern side of the region. Precipitation has trended downward for much of the region since 1975, but relatively little change in precipitation is projected between the 2020s and the 2060s. Under the higher emissions “Paris Forever” scenario, we found that by the 2060s, the 1-in-20-year low-rainfall events will occur twice as frequently in most of the region, though it will occur less frequently in northwestern Angola. The 1-in-20-year high-rainfall events will occur 3 to 4 times as often in northeastern South Africa and twice as often in most of Angola.
Angiopoietin-Like Protein 4 May Be an Interplay Between Serum Uric Acid and Triglyceride-Rich Lipoprotein Cholesterol
Authors: Peng Yani , Hu Die , Luo Qingting , Peng Daoquan
Published: June 2022

Background

Although the available evidence has indicated a link between elevated serum uric acid (SUA) level and dyslipidemia, the potential contribution of SUA on lipid profiles remains unclear. Experimental and clinical studies have revealed several mechanisms through which high serum angiopoietin-like protein 4 (ANGPTL4) level exerts deleterious effects on lipid metabolism, but the role of ANGPTL4 in SUA-associated dyslipidemia has not been well studied, so far.

Methods

A total of 80 subjects were classified into high SUA group (n = 40) and low SUA group (n = 40) by the median value of SUA in the whole study population. Serum ANGPTL4 levels were determined by enzyme-linked immunosorbent assays.

Results

In our study, we observed that not only serum triglyceride level [1.03 (0.78, 1.50) mmol/L vs. 1.59 (1.18, 2.37) mmol/L, p = 0.001] but also serum triglyceride-rich lipoprotein cholesterol (TRL-C) level [0.38 (0.32, 0.45) mmol/L vs. 0.46 (0.34, 0.54) mmol/L, p = 0.012] were significantly elevated in high SUA group. Additionally, serum ANGPTL4 in high SUA group was higher than in low SUA group [15.81 (11.88, 20.82) ng/ml vs. 22.13 (17.88, 32.09) ng/ml, p = 0.000]. Moreover, in all subjects, TRL-C levels were positively associated with SUA (r = 0.26, p = 0.023, n = 80) and ANGPTL4 levels (r = 0.24, p = 0.036, n = 80). Using stepwise multiple regression analysis to adjust for potential confounders, SUA was discovered to be an independent contributor to serum ANGPTL4 (p = 0.023). At the same time, serum ANGPTL4 was an independent contributor to the level of TRL-C (p = 0.000). However, the correlation between SUA and TRL-C disappeared after controlling for ANGPTL4 level.

Conclusion

Serum uric acid was positively correlated to TRL-C. ANGPTL4 may be an interplay between SUA and associated elevation of TRL-C.
Unmet Needs in Patients With Heart Failure: The Importance of Palliative Care in a Heart Failure Clinic
Authors: Gonzalez-Jaramillo Valentina , Maessen Maud , Luethi Nora , Guyer Jelena , Hunziker Lukas , Eychmüller Steffen , Zambrano Sofia C.
Published: June 2022

Background

There are increasing calls to establish heart failure (HF) clinics due to their effectiveness in the interdisciplinary management of people living with HF. However, although a recommendation exists for palliative care (PC) providers to be part of the interdisciplinary team, few of the established HF clinics include them in their teams. Therefore, in this qualitative study, we aimed to understand the unmet PC needs of patients with HF attending an already established HF clinic.

Methods

Secondary qualitative analysis of structured interviews undertaken within a larger study to validate the German version of the Needs Assessment Tool: Progressive Disease—Heart Failure (NAT: PD-HF). The NAT: PD-HF is a tool that aims to assess unmet needs in patients with HF. The interviews took place between January and March 2020 with patients from the ambulatory HF Clinic of a University Hospital in Switzerland. For this analysis, we transcribed and thematically analyzed the longest and most content-rich interviews until we reached data saturation at 31 participants. The interviews lasted 31 min on average (24–48 min).

Results

Participants (n= 31) had a median age of 64 years (IQR 56–77), the majority had reduced ejection fraction, were men, and were classified as having a New York Heart Association functional class II. Participants were in general satisfied with the treatment and information received at the HF clinic. However, they reported several unmet needs. We therefore identified three ambivalences as main themes: (I) “feeling well-informed but missing essential discussions”, (II) “although feeling mostly satisfied with the care, remaining with unmet care needs”, and (III) “fearing a referral to palliative care but acknowledging its importance”.

Conclusion

Although patients who are receiving multidisciplinary management in ambulatory HF clinics are generally satisfied with the care received, they remain with unmet needs. These unmet needs, such as the need for advance care planning or the need for timely and tactful end-of-life discussions, can be fulfilled by PC providers. Including personnel trained in PC as part of the multidisciplinary team could help to address patients' needs, thus improving the quality of care and the quality of life of people living with HF.
A Nomogram for Predicting Survival in Patients With Colorectal Cancer Incorporating Cardiovascular Comorbidities
Authors: Wang Hao , Liu Dong , Liang Hanyang , Ba Zhengqing , Ma Yue , Xu Haobo , Wang Juan , Wang Tianjie , Tian Tao , Yang Jingang , Gao Xiaojin , Qiao Shubin , Qu Yanling , Yang Zhuoxuan , Guo Wei , Zhao Min , Ao Huiping , Zheng Xiaodong , Yuan Jiansong , Yang Weixian
Published: June 2022

Background

Cardiovascular comorbidities (CVCs) affect the overall survival (OS) of patients with colorectal cancer (CRC). However, a prognostic evaluation system for these patients is currently lacking.

Objectives

This study aimed to develop and validate a nomogram, which takes CVCs into account, for predicting the survival of patients with CRC.

Methods

In total, 21,432 patients with CRC were recruited from four centers in China between January 2011 and December 2017. The nomogram was constructed, based on Cox regression, using a training cohort (19,102 patients), and validated using a validation cohort (2,330 patients). The discrimination and calibration of the model were assessed by the concordance index and calibration curve. The clinical utility of the model was measured by decision curve analysis (DCA). Based on the nomogram, we divided patients into three groups: low, middle, and high risk.

Results

Independent risk factors selected into our nomogram for OS included age, metastasis, malignant ascites, heart failure, and venous thromboembolism, whereas dyslipidemia was found to be a protective factor. The c-index of our nomogram was 0.714 (95% CI: 0.708–0.720) in the training cohort and 0.742 (95% CI: 0.725–0.759) in the validation cohort. The calibration curve and DCA showed the reliability of the model. The cutoff values of the three groups were 68.19 and 145.44, which were also significant in the validation cohort (p < 0.001).

Conclusion

Taking CVCs into account, an easy-to-use nomogram was provided to estimate OS for patients with CRC, improving the prognostic evaluation ability.
Single Cell Transcriptomic Analysis Reveals Organ Specific Pericyte Markers and Identities
Authors: Baek Seung-Han , Maiorino Enrico , Kim Hyunbum , Glass Kimberly , Raby Benjamin A. , Yuan Ke
Published: June 2022

Pericytes are mesenchymal-derived mural cells that wrap around capillaries and directly contact endothelial cells. Present throughout the body, including the cardiovascular system, pericytes are proposed to have multipotent cell-like properties and are involved in numerous biological processes, including regulation of vascular development, maturation, permeability, and homeostasis. Despite their physiological importance, the functional heterogeneity, differentiation process, and pathological roles of pericytes are not yet clearly understood, in part due to the inability to reliably distinguish them from other mural cell populations. Our study focused on identifying pericyte-specific markers by analyzing single-cell RNA sequencing data from tissue-specific mouse pericyte populations generated by the Tabula Muris Senis. We identified the mural cell cluster in murine lung, heart, kidney, and bladder that expressed either of two known pericyte markers, Cspg4 or Pdgfrb. We further defined pericytes as those cells that co-expressed both markers within this cluster. Single-cell differential expression gene analysis compared this subset with other clusters that identified potential pericyte marker candidates, including Kcnk3 (in the lung); Rgs4 (in the heart); Myh11 and Kcna5 (in the kidney); Pcp4l1 (in the bladder); and Higd1b (in lung and heart). In addition, we identified novel markers of tissue-specific pericytes and signaling pathways that may be involved in maintaining their identity. Moreover, the identified markers were further validated in Human Lung Cell Atlas and human heart single-cell RNAseq databases. Intriguingly, we found that markers of heart and lung pericytes in mice were conserved in human heart and lung pericytes. In this study, we, for the first time, identified specific pericyte markers among lung, heart, kidney, and bladder and reveal differentially expressed genes and functional relationships between mural cells.
Comparative Safety and Effectiveness of Ticagrelor versus Clopidogrel in Patients With Acute Coronary Syndrome: An On-Treatment Analysis From a Multicenter Registry
Authors: Almendro-Delia Manuel , Blanco-Ponce Emilia , Carmona-Carmona Jesús , Arboleda Sánchez J. A. , Rodríguez Yáñez Juan Carlos , Soto Blanco José Manuel , Fernández García Isabel , Castillo Caballero José M. , García-Rubira Juan C. , Hidalgo-Urbano Rafael J.
Published: June 2022

Background:

The net clinical benefit of ticagrelor over clopidogrel in acute coronary syndrome (ACS) has recently been questioned by observational studies which did not account for time-dependent confounders. We aimed to assess the comparative safety and effectiveness of ticagrelor vs. clopidogrel accounting for non-adherence in a real-life setting.

Methods

This is a prospective, multicenter cohort study of patients with ACS discharged on ticagrelor or clopidogrel between 2015 and 2019. Major exclusions were previous intracranial bleeding, and the use of prasugrel or oral anticoagulation. Association of P2Y12 inhibitor therapy with 1-year risk of Bleeding Academic Research Consortium Type 3 or 5 bleeding; major adverse cardiac events (MACEs), a composite endpoint of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, or urgent target lesion revascularization; definite/probable stent thrombosis; vascular death; and net adverse clinical event (a composite endpoint of major bleeding and MACE) were analyzed according to the “on-treatment” principle, using fully adjusted Cox and Fine-Gray regression models with doubly robust inverse probability of censoring weighted estimators.

Results

Among 2,070 patients (mean age 63 years, 27% women, 62.5% ST-elevation MI), 1,035 were discharged on ticagrelor and clopidogrel, respectively. Ticagrelor-treated patients were younger and had few comorbidities, but high rates of medication non-compliance, compared with clopidogrel users. After comprehensive multivariate adjustments, ticagrelor did not increase the risk of major bleeding compared with clopidogrel [subhazard ratio, 1.40; 95% confidence interval (CI), 0.96–2.05], while proved superior in reducing MACE (hazard ratio 0.62; 95% CI, 0.43–0.90), vascular death (subhazard ratio, 0.71; 95% CI, 0.52–0.97) and definite/probable stent thrombosis (subhazard ratio, 0.54; 95% CI, 0.30-0.79); thereby resulting in a favorable net clinical benefit (hazard ratio 0.78; 95% CI, 0.60–0.98) compared with clopidogrel. Results from sensitivity analyses were consistent with those from the primary analysis, whereas those from the intention-to-treat (ITT) analysis went in the opposite direction.

Conclusion

Among all-comers with ACS, ticagrelor did not significantly increase the risk of major bleeding, while resulting in a net clinical benefit compared with clopidogrel. Further research is warranted to confirm these findings in high bleeding risk populations.

CREA-ARIAM Andalucía

(ClinicalTrials.gov Identifier: NCT02500290); Current pre-specified analysis (ClinicalTrials.gov Identifier: NCT04630288).