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The COVID-19 pandemic has significantly impacted global health, especially in vulnerable populations like kidney transplant recipients (KTRs). Recently, mass spectrometry-based proteomics has emerged as a powerful tool to shed light on a broad spectrum of dysregulated biological processes in KTRs with COVID-19. In this study, we prospectively collected blood samples from 17 COVID-19-positive KTRs and 10 non-infected KTRs between May and September 2020. Using tandem mass tag-based quantitative proteomics, we analyzed peripheral blood mononuclear cells (PBMCs), plasma protein biomarkers, and lymphocyte counts, followed by bioinformatics analysis. Our results revealed significant proteomic alterations in COVID-19-infected KTRs, particularly in pathways related to glycolysis, glucose metabolism, and neutrophil degranulation. Additionally, we observed an altered immune response characterized by elevated cytokines and decreased lymphocyte counts. Notably, KTRs with AKI exhibited worse clinical outcomes, including higher rates of ICU admission and mechanical ventilation. Comparative analysis of PBMC proteomic profiles between AKI and non-AKI patients identified distinct immune-related pathways, with AKI patients showing marked changes in innate immune responses, particularly neutrophil degranulation. Furthermore, we observed a negative correlation between T cell counts and neutrophil degranulation, suggesting a role for immune dysregulation in COVID-19. Our findings provide critical insights into the immune and metabolic responses in COVID-19-infected KTRs, especially those with AKI, highlighting the need for focused research and therapeutic strategies targeting immune dysregulation in this high-risk population.

Abstract Long–chain polyunsaturated fatty acids (LCPUFA) are of interest due to their potential health properties and have a significant role in reducing the risk of various chronic diseases in humans. It is commonly used as a supplement. However, lipid oxidation is an important negative factor caused by environmental, processing, and limited water solubility of LCPUFA, making them difficult to incorporate into food products. The objective of this research work was to prevent oxidation, extend shelf life, enhance the stability of fatty acids, and to achieve controlled release by preparing spray-dried powder (SDM). For spray-drying, aqueous emulsion blends were formulated using a 1:1 ratio of chia seed oil (CSO) and fish oil (FO) and using a laboratory-scale spray–dryer with varying conditions: inlet air temperature (IAT, 125–185 °C), wall material (WM, 5–25%), pump speed (PS, 3–7 mL/min), and needle speed (NS, 3–11 s). The maximum alpha-linolenic acid (ALA) content was 33 ± 1%. The highest values of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the microcapsules were 8.4 ± 0.4 and 13 ± 1%, respectively. Fourier transform infrared and X-Ray diffraction analysis results indicated that SDM was successfully formulated with Gum Arabic and maltodextrin (MD). The blending without encapsulation of CSO and FO was digested more efficiently and resulted in more oil being released with simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and SGF + SIF conditions without heating. No significant changes were observed for saturated, monounsaturated, and LCPUFA, whether exposed or not to gastrointestinal conditions. However, compared to the release of SDM, it can be useful for designing delivery systems for the controlled release of essential fatty acids.

Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease. Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18–45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs. placebo in decreasing the rate of structural knee changes and pain. Participants will be asked to take up to 1500 ​mg/day of either metformin or placebo as tolerated. The primary outcomes are Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale scores averaged between 12 and 24 months after randomization, and MRI derived cartilage structural change at 24 months. The trial will be deemed successful if at least one of the two primary outcomes reaches the preplanned effect size with sufficient statistical certainty. In this paper, we describe PIKASO elements according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Results: Our multidisciplinary team developed the methods and statistical analysis plan for a placebo controlled, randomized clinical trial to determine whether metformin alters pain and early osteoarthritic changes after ACLR. Discussion: This manuscript outlines the rationale, study design, and implementation of the PIKASO trial aiming to prevent the onset of PTOA after ACLR. Trial registration: clinicaltrials.gov NCT06096259.

Competing uses for nearshore coastal space, such as aquaculture, have complex environmental and ecological interactions with surrounding seagrass meadows. Oyster aquaculture is among the fastest-growing aquaculture segments in the United States, and it brings concerns such as increased sedimentation from farm maintenance operations and altered water quality through oyster filtration. Changes in seagrass coverage and growth are common indicators of ecological health used to determine anthropogenic impacts on nearshore environments. This study characterized the effects of a research-scale adjustable long-line oyster aquaculture system on the health of adjacent seagrass meadows in Copano Bay, TX. Four Halodule wrightii meadows were identified at various distances from the research site: 100 m upstream (upstream), directly adjacent (0 m), 30 m downstream (30 m), and 60 m downstream (60 m). Sites were monitored for 1) seagrass health, 2) water quality parameters, and 3) sediment deposition. Over the 18-week sampling period, no significant differences (p>0.05) were found for water quality variables or sediment grain-size analysis using a one-way ANOVA. A linear mixed-effects model was used for repeated measures of seagrass data, with no effect of the site found on mean seagrass length, coverage, or maximum length (p>0.05). These results suggest that seagrass health indicators were unaffected by proximity to the oyster system. It was concluded that an oyster research aquaculture system of the type and size at the project location had no major negative or positive impact on seagrass meadow health due to high background variability and the overall minor footprint of the oyster farm across a comparatively large spatial extent.

Summary: Airway epithelial cells represent the first line of defense against respiratory pathogens. Flagellin drives the motility of many mucosal pathogens and has been suggested as an immune enhancing adjunctive therapeutic in infections of the airways. This study leveraged single-cell RNA sequencing to determine cell-specific effects of flagellin in primary human bronchial epithelial cells growing in air-liquid interface. Seven cell clusters were identified, including ciliated cells, ionocytes, and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells demonstrated a proportional increase in response to flagellin. Inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, while in inflammatory basal cells transcriptome profiles indicated enhanced oxidative phosphorylation. Inhibition of mTOR prevented the shift to glycolysis and reduced inflammatory gene transcription specifically in inflammatory secretory cells. These data demonstrate the functional heterogeneity of the human airway epithelium upon exposure to flagellin.

There are several key points clinicians should consider when managing patients with overlapping thyroid and renal disease. Patients who are euthyroid and have chronic kidney disease (CKD) may physiologically have normal-high thyroid stimulating hormone (TSH), low free thyroxine (FT4), low free triiodothyronine (FT3) and normal-low reverse triiodothyronine (rT3). Untreated subclinical and primary hypothyroidism among patients with (CKD) is associated with reversible progression of renal failure. Supplementing these (CKD) patientswith levothyroxine can delay the progression of renal failure and prevent end stage renal disease (ESRD). Untreated hyperthyroidism increases the glomerular filtration rate (GFR) by 18 to 25%. Thus, the management of hyperthyroidism may unmask patients with undiagnosed CKD. There is no dosage adjustment required for methimazole among patients with CKD. However, methimazole may be eliminated during hemodialysis (HD) by around 30 to 40%. Patients with papillary thyroid cancer and ESRD may have higher rates of aggressive characteristics. Patients with CKD and ESRD undergoing radioiodine I-131 treatment for thyroid cancer are at increased risk of prolonged radiation transmission risk due to decreased iodine urinary excretion. Additionally, the optimal dosing and timing of radioiodine I-131 therapy amongst patients with ESRD and thyroid cancer requires further research. The use dosimetry studies and multidisciplinary coordination among nuclear medicine, nephrology and endocrinology is recommended for these patients.

Gratitude has been extensively studied over the past two decades. Among several predictors, aspects of religiosity and spirituality have been consistent predictors of gratitude. To explore the religious motivations and processes that foster the practice of gratitude, we undertook a systematic thematic analysis using interview data from a national qualitative project of 198 highly religious families. Participants (n = 476) included mothers, fathers, and children from various socioeconomic backgrounds and from diverse religious, racial, and ethnic backgrounds in the United States of America. Semi-structured interviews were conducted in the participants’ homes. Data for this study were analyzed using a team-based approach to qualitative analysis. The findings were organized thematically, including: (a) aspects of gratitude, (b) expressions of gratitude, and (c) the influence of gratitude. Two aspects of gratitude were identified: functional—what people were grateful for—and directional—to whom they were grateful. Expressions of gratitude involved participation in regular, gratitude-focused prayers and mutual day-to-day appreciation. The relational context and implications and context of gratitude in religious families were further examined and reported with sub-themes: (a) gratitude prompted positive re-evaluation of relationships and (b) gratitude reinforced religious faith. Implications, strengths, limitations, and future directions are discussed.

Frozen storage of emulsion-type sausages may be one approach to avoid or reduce the use of sodium nitrite, which is associated with health risks. Silver carp (Hypophthalmichthys molitrix) mince (M0) was washed for 1 (M1) or 3 (M3) times and the impact of washing on the properties frozen storage (−18 °C) during 4 months were determined and results were compared to those of conventional silver carp sausages (Mt). Lipid oxidation, as evidenced by changes in thiobarbituric acid reactive substances and FFAs, took place during storage in the order of M0 > M1 = M3 = Mt with M0 being highly oxidized (P ≤ 0.05). Total volatile base nitrogen formed during storage and the ranking for the quality loss was as follows M0 > M1 > M3 = Mt. Washing (M1 = M3) led to less hardness (P ≤ 0.05). Mt had better redness, while M1 and M3 led to higher expressible moisture, water release and lightness (P ≤ 0.05). Results indicated the lower sensory and consumer-liking properties of frozen M1 and M3 sausages. Therefore, washing and frozen storage influenced silver carp mince sausages.

Background: Despite attempts to control malaria, poor drug bioavailability means malaria still places enormous pressure on health globally. It has been found that the solubility of highly lipophilic compounds can be enhanced through lipid formulations, e.g., self-emulsifying drug delivery systems (SEDDSs). Thus, quality-by-design and characterization were used to justify the development and determine the feasibility of oral oil-in-water SEDDSs comprising a fixed-dose combination (FDC) of artemether–lumefantrine to treat malaria more effectively without the aid of a fatty meal. These formulations were compared to a commercial product containing the same active compounds. Methods: Excipient compatibility and spontaneous emulsification capacity of different FDC–excipient combinations were identified by employing isothermal microcalorimetry, solubility, and water titration tests. Pseudoternary phase diagrams were constructed, and checkpoint formulations were selected within the self-emulsification region by reviewing formulation properties essential for optimized drug delivery. SEDDSs capable of enduring phase separation within 24 h were subjected to characterization experiments, i.e., drug concentration determination, cloud point, droplet size, size distribution, self-emulsification time, self-emulsification efficacy, viscosity, zeta potential, and thermodynamic stability analysis. SEDDSs with favorable characteristics were identified in the micro or nano range (SNEDDSs) before being subjected to drug release studies. Results: All final formulations depicted enhanced artemether and lumefantrine release compared to the commercial product, which could not release lumefantrine at a quantifiable concentration in this study. The avocado oil (AVO)4:6 and olive oil (OLV)3:7 SNEDDSs overall portrayed the ideal characteristics and depicted the highest percentage of drug release. Conclusions: This study offers evidence that SNEDDSs from selected natural oils comprising an artemether–lumefantrine FDC can potentially enhance the bioavailability of these lipophilic drugs.

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour's response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies.

ABSTRACTThe structural behaviour of Glass Fibre Reinforced Polymer (GFRP) retrofitted reinforced concrete beam in addition with Nano admixtures (NA) was experimentally investigated and analysed. Globally, a large number of structures are subjected to unanticipated damages and deterioration. To renovate such buildings to serviceable state, repairing and retrofitting of damaged structures is the viable and economical option. This investigation aims to improve the resistance to flexure for reinforced beam by enhancing the mechanical properties concrete with the addition of various combinations of Nano admixtures (NA) as Nano silica (NS) and Nano clay (NC) and retrofitting the same. The void filling property of Nano admixtures produced a dense concrete with minimum voids in the concrete mass and improved the mechanical properties. To analyse the influence of Nano admixture, SEM analysis was done and the micro structure of the concrete mix was studied and analysed the microstructural features of the concrete. The structural mechanism of beams before and after wrapped with two layers of GFRP sheets was experimentally verified by this study.

Abstract Background The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis. Methods We analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals. Results Older age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients

Abstract Biofouling is a major global environmental and economic challenge wherein organisms settle on solid surfaces submerged in natural waters. This leads to the spread of invasive marine species around the globe, accelerates surface deterioration through microbially‐induced corrosion, and inflates maritime vessel fuel consumption which leads to greater greenhouse gas emissions. In this study, pulsed plasma poly(styrene) nanocoatings impregnated with eco‐friendly liquids are produced that yield slippery surfaces through aromatic–aliphatic intermolecular interactions (water droplet contact angle hysteresis and sliding angle values ≈1–2°). The antibiofouling performance of these slippery surfaces is demonstrated using laboratory‐based marine bioassays and real‐world field trials in freshwater (pond water) and seawater (ocean) environments. Low‐cost and substrate‐independent pulsed plasmachemical deposition combined with eco‐friendly liquid impregnation provides a sustainable approach to tackling environmental biofouling.

In this study, oil-in-water emulsions stabilized by insoluble dietary fibre from citrus peel (CIDF) exhibited an obviously delayed lipid digestion property through gastrointestinal tract (GIT) model. Our results suggested that the rate and extent of lipid digestion greatly relied on particle sizes and concentrations of CIDF, and the inhibition effect of lipolysis was markedly enhanced with decreasing particle sizes and increasing CIDF levels. Furthermore, compared with Tween80-stabilized emulsion, the maximum inhibition extent of lipolysis was 38.77% for CIDF400-stabilized one at 0.4 wt% concentration. Effects of CIDFs on lipid digestion was mainly due to the formation of protective layers around oil droplets, further blocking the entry of lipase to the internal lipids, and/or attributed to the increasing viscosity of emulsions caused by CIDFs, finally limiting the transportation of some substances in the simulated small intestine digestion. Our research would provide useful references for the application of CIDF-stabilized emulsions in low-calorie food.

Providing food has become more complex because of climate change and other environmental and societal stressors, such as political instability, the growth in the world population, and outbreaks of new diseases, especially the COVID-19 pandemic. In response to these challenges, the agri-food industry has increased its efforts to shift to using more digital tools and other advanced technologies. The transition toward digital has been part of the fourth industrial revolution (called Industry 4.0) innovations that have and are reshaping most industries. This literature review discusses the potential of implementing digital technologies in the agri-food industry, focusing heavily on the role of the COVID-19 pandemic in fostering the adoption of greater digitalization of food supply chains. Examples of the use of these digital innovations for various food applications, and the barriers and challenges will be highlighted. The trend toward digital solutions has gained momentum since the advent of Industry 4.0 and implementations of these solutions have been accelerated by the outbreak of the COVID-19 pandemic. Important digital technology enablers that have high potential for mitigating the negative effects of both the current global health pandemic and the environmental crisis on food systems include artificial intelligence, big data, the Internet of Things, blockchain, smart sensors, robotics, digital twins, and virtual and augmented reality. However, much remains to be done to fully harness the power of Industry 4.0 technologies and achieve widespread implementation of digitalization in the agriculture and food industries.

Summary: Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients’ neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.

In the actual production process of soy protein isolate (SPI), most of the homogeneous operating pressure is controlled below 20 MPa due to the consideration of production safety and the limitation of the pressure control capability of homogeneous equipment. In order to improve the functional properties of SPI and adapt it to actual production, the effects of different homogeneous pressures (4, 8, 10, 12, and 14 MPa) on the structure and gel properties of SPI were studied from the perspective of production control. Compared to the control group, the modified SPI improved the hardness, springiness, cohesiveness, chewiness, and water holding capacity (WHC) of the protein gel (p < 0.05). Rheological analysis shows that both G′ and G″ increase with increasing frequency, reaching a maximum at 12 MPa. The gel intermolecular force results show that the disulfide bond, hydrophobic interaction, and non-disulfide bond are important molecular forces for gel formation. The particle size distribution uniformity of modified SPI was high, and scanning electron microscopy (SEM) analysis showed that the protein gel with a continuous uniform and dense network structure could be formed by high-pressure homogeneous modification. Overall, high-pressure homogenization technology has the potential to improve SPI gel structure and WHC, and 12 MPa modified SPI gel has the most significant effect.

Fish processing by-products such as frames, trimmings, and viscera of commercial fish species are rich in proteins. Thus, they could potentially be an economical source of proteins that may be used to obtain bioactive peptides and functional protein hydrolysates for the food and nutraceutical industries. The structure, composition, and biological activities of peptides and hydrolysates depend on the freshness and the actual composition of the material. Peptides isolated from fishery by-products showed antioxidant activity. Changes in hydrolysis parameters changed the sequence and properties of the peptides and determined their physiological functions. The optimization of the value of such peptides and the production costs must be considered for each particular source of marine by-products and for their specific food applications. This review will discuss the functional properties of fishery by-products prepared using hydrolysis and their potential food applications. It also reviews the structure–activity relationships of the antioxidant activity of peptides as well as challenges to the use of fishery by-products for protein hydrolysate production.

From 1995–2016, there has been a 15-fold increase in qualitative scholarship in the social sciences, but the rigor and quality of published work has ranged widely. Little scholarship provides concrete, pragmatic explanations of (and directions regarding) the execution of systematic, high-rigor qualitative analysis. The present article guides the developing qualitative researcher through technical and procedural aspects of analyzing qualitative data with specific attention to reliability and rigor. Guidance addressing transcription, importing data, forming coding pairs, performing initial/open coding (examples of three types), determining core themes, systematic team-based coding, maintaining a data audit trail, creating a Numeric Content Analysis (NCA) table, and preparing work for publication is provided. Materials include several tables and figures that offer practical demonstrations on how to use Nvivo in data analysis. Transcription tips and outsourcing benefits and cautions are also offered. Altogether, the present article provides qualitative researchers practical guidance for executing multiple stages of qualitative analysis.

Radium-223 dichloride (223Ra) is an α-emitter approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, but without visceral involvement. Despite being a life-prolonging therapy (LPT), 223Ra remains underutilized. A large body of real-world evidence (RWE) for 223Ra has been published in the decade since the pivotal phase 3 ALSYMPCA study, a period during which the treatment landscape has continued to evolve. How to optimize 223Ra use, including how to integrate it into the mCRPC management pathway amongst other current LPTs (i.e., with respect to timing and concurrent, layered, or sequential use), is therefore of considerable interest. RWE studies lack the conventional restraints of clinical trials and can therefore help to build an understanding of how treatments may be best used in routine practice. Here we review RWE studies investigating the efficacy and safety of 223Ra in mCRPC [including in sequence with the recently approved 177-Lutetium conjugated to the ligand prostate-specific membrane antigen (177Lu-PSMA)], as well as response marker development, imaging techniques, and current clinical practice recommendations.

We describe the development and validation of a new high performance liquid chromatography (HPLC) method for analysis of a combination of the first-line anti-tubercular drugs isoniazid, pyrazinamide, and rifampicin together with clofazimine. This is a unique challenge since clofazimine and rifampicin are relatively highly lipophilic drugs, whereas isoniazid and pyrazinamide are considerably more hydrophilic. Thus, clear separation of peaks and quantification of four individual drugs can present difficulties during the development of an analytical method. Detection was established at two wavelengths—254 nm for isoniazid and pyrazinamide and 320 nm for clofazimine and rifampicin. Gradient elution was employed using 0.1% aqueous formic acid (A) and acetonitrile (B); clear separation of the four drugs was achieved within 10 min. A linear relationship was indicated by a correlation coefficient (r2) of 0.9999 for each anti-tubercular drug, respectively. The limit of detection (LOD) for the individual drugs was 0.70 µg/mL (isoniazid), 0.30 µg/mL (pyrazinamide), 0.20 µg/mL (rifampicin) and 0.20 µg/mL (clofazimine). Precision experiments rendered a mean recovery percentage of 101.25% (isoniazid), 98.70% (pyrazinamide), 99.68% (rifampicin) and 97.14% (clofazimine). This HPLC method was validated and is reliable, repeatable, and accurate for the purpose of conducting simultaneous HPLC analyses of the four anti-tubercular drugs.

Self-emulsifying drug delivery systems (SEDDSs) are lipid-based systems that are superior to other lipid-based oral drug delivery systems in terms of providing drug protection against the gastrointestinal (GI) environment, inhibition of drug efflux as mediated by P-glycoprotein, enhanced lymphatic drug uptake, improved control over plasma concentration profiles of drugs, enhanced stability, and drug loading efficiency. Interest in dermal spontaneous emulsions has increased, given that systems have been reported to deliver drugs across mucus membranes, as well as the outermost layer of the skin into the underlying layers. The background and development of a double spontaneous emulsion incorporating four anti-tubercular drugs, clofazimine (CFZ), isoniazid (INH), pyrazinamide (PZY), and rifampicin (RIF), are described here. Our methods involved examination of oil miscibility, the construction of pseudoternary phase diagrams, the determination of self-emulsification performance and the emulsion stability index of primary emulsions (PEs), solubility, and isothermal micro calorimetry compatibility and examination of emulsions via microscopy. Overall, the potential of self-double-emulsifying drug delivery systems (SDEDDSs) as a dermal drug delivery vehicle is now demonstrated. The key to success here is the conduct of preformulation studies to enable the development of dermal SDEDDSs. To our knowledge, this work represents the first successful example of the production of SDEDDSs capable of incorporating four individual drugs.

Abstract In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

Background: Recent paradigm shifts in postpartum care have conceptualized the ?fourth trimester? as a critical transitional period requiring tailored, ongoing health care. However, this concept presents challenges for providers, especially in low-resource settings. Our objective was to understand providers' perspectives on challenges in postpartum care to highlight strategies for optimizing care. Methods: Focus groups were conducted using a semistructured interview guide to elicit perspectives on barriers and facilitators to postpartum care. Participants included physicians, nurses, and social workers who care for low-income postpartum individuals. Interviews explored the provider experience of postpartum care, with a focus on barriers experienced by patients and providers, and tools for maintaining engagement. Analysis was performed using the constant comparative method and framed by the Social Ecological Model. Results: Participants (N?=?26) all acknowledged the importance of the ?fourth trimester? but identified multiple barriers to providing optimal postpartum care. Challenges providers perceived for patients and those they perceived for themselves often overlapped, including difficulty with appointment scheduling, insurance limitations, lack of provider continuity, and knowledge gaps. Providers identified ease of referrals to specialists, access to tangible services (e.g., contraception), and enhanced care coordination (e.g., patient navigation) as potential facilitators of improved postpartum care. Conclusions: Obstetric providers recognize the importance of postpartum care yet highlighted significant systems- and patient-based barriers to achieving optimal care. The development and implementation of postpartum care delivery system redesign, such as the use of patient navigators to improve health care utilization and resource attainment, may enhance care during this critical time. Clinical Trial No.: NCT03922334.

Abstract The pathophysiology of sepsis is multi-facetted and highly complex. As sepsis is a leading cause of global mortality that still lacks targeted therapies, increased understanding of its pathogenesis is vital for improving clinical care and outcomes. An increasing number of investigations seeks to unravel the complexity of sepsis through high-dimensional data analysis, enabled by advances in -omics technologies. Here, we summarize progress in the following major -omics fields: genomics, epigenomics, transcriptomics, proteomics, lipidomics, and microbiomics. We describe what these fields can teach us about sepsis, and highlight current trends and future challenges. Finally, we focus on multi-omics integration, and discuss the challenges in deriving biological meaning and clinical applications from these types of data.

Proximal junctional kyphosis (PJK) is a difficult complication to manage following adult spinal deformity surgery. Particularly in spinal fusions from the lower thoracic spine down to pelvis, PJK is a major consideration. While the open posterior approach allows for excellent visualization and preparation of bony surfaces for fusion, disruption of posterior soft tissue structures increases risk of PJK postoperatively. Minimally invasive approaches, on the other hand, preserve posterior ligamentous structures and musculature at the proximal fusion levels however prevent the access afforded by an open approach. We describe here the hybrid open muscle-sparing approach—a technique that allows for decortication of bony surfaces as well as clear exposure of anatomic landmarks for freehand pedicle screw placement, while protecting the posterior soft tissue structures to reduce risk of PJK.

Summary: Human studies describing the immunomodulatory role of the intestinal microbiota in systemic infections are lacking. Here, we sought to relate microbiota profiles from 115 patients with community-acquired pneumonia (CAP), both on hospital admission and following discharge, to concurrent circulating monocyte and neutrophil function. Rectal microbiota composition did not explain variation in cytokine responses in acute CAP (median 0%, IQR 0.0%–1.9%), but did one month following hospitalization (median 4.1%, IQR 0.0%–6.6%, p = 0.0035). Gene expression analysis of monocytes showed that undisrupted microbiota profiles following hospitalization were associated with upregulated interferon, interleukin-10, and G-protein-coupled-receptor-ligand-binding pathways. While CAP is characterized by profoundly distorted gut microbiota, the effects of these disruptions on cytokine responses and transcriptional profiles during acute infection were absent or modest. However, rectal microbiota were related to altered cytokine responses one month following CAP hospitalization, which may provide insights into potential mechanisms contributing to the high risk of recurrent infections following hospitalization.

The growing consumer awareness of climate change and the resulting food sustainability issues have led to an increasing adoption of several emerging food trends. Some of these trends have been strengthened by the emergence of the fourth industrial revolution (or Industry 4.0), and its innovations and technologies that have fundamentally reshaped and transformed current strategies and prospects for food production and consumption patterns. In this review a general overview of the industrial revolutions through a food perspective will be provided. Then, the current knowledge base regarding consumer acceptance of eight traditional animal-proteins alternatives (e.g., plant-based foods and insects) and more recent trends (e.g., cell-cultured meat and 3D-printed foods) will be updated. A special focus will be given to the impact of digital technologies and other food Industry 4.0 innovations on the shift toward greener, healthier, and more sustainable diets. Emerging food trends have promising potential to promote nutritious and sustainable alternatives to animal-based products. This literature narrative review showed that plant-based foods are the largest portion of alternative proteins but intensive research is being done with other sources (notably the insects and cell-cultured animal products). Recent technological advances are likely to have significant roles in enhancing sensory and nutritional properties, improving consumer perception of these emerging foods. Thus, consumer acceptance and consumption of new foods are predicted to continue growing, although more effort should be made to make these food products more convenient, nutritious, and affordable, and to market them to consumers positively emphasizing their safety and benefits.

IntroductionRadium-223 (223Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223Ra at the cellular level.MethodsWe evaluated the effects of 223Ra irradiation in a panel of cell lines and then compared them with standard X-ray and external alpha-particle irradiation, with a particular focus on cell survival and DNA damage repair kinetics.Results223Ra exposures had very high, cell-type-dependent RBE50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe.ConclusionsThese results suggest that 223Ra exposure may be associated with greater biological effects than would be expected by direct comparison with a similar dose of external alpha particles, highlighting important challenges for future therapeutic optimization.

Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544. Chris C Parker and colleagues report long-term findings on overall survival and local complications in men with metastatic prostate cancer treated with radiotherapy. Author summary Why was this study done? Prostate cancer is the most common cancer in males. Radiotherapy (RT) to the prostate is widely used as a radical treatment for nonmetastatic prostate cancer. A comparison was added to the STAMPEDE protocol to assess whether RT to the prostate would also be helpful for males with metastatic prostate cancer. A benefit in survival was targeted. The trial previously reported a clinically relevant, statistically significant overall survival (OS) benefit for patients with a low metastatic burden but not for men with a high metastatic burden. This long-term analysis assesses survival with substantially longer follow-up and more events and looked also at complications of local disease. What did the researchers do and find? A randomised controlled trial of adding RT to the prostate to standard of care (SOC) was incorporated into the STAMPEDE protocol. More than 2,000 patients joined the comparison between 2013 and 2016. The data set was frozen in 2021 and analysed using standard methods. There was a clear improvement in survival with prostate RT in the low metastatic burden group. There was no improvement in survival with prostate RT in the high metastatic burden group. Symptomatic local progression and the need for later local intervention were improved with RT in the low metastatic burden group. In the low metastatic burden group, the improvement with RT was similar whether the RT was given with a daily schedule (over 4.5 weeks) or a weekly schedule (over 6 weeks). The adverse effects of RT were manageable without any impact on long-term quality of life (QoL). What do these findings mean? Prostate RT is a relatively cheap, widely accessible, and well-tolerated treatment. Prostate RT is indicated in patients with newly diagnosed prostate cancer with a low metastatic burden. RT to the prostate is not routinely indicated for patients with a high metastatic burden.

The coronavirus disease (COVID-19) pandemic caused several negative impacts on global human health and the world’s economy. Food and seafood safety and security were among the principal challenges and causes of concern for the food industry and consumers during the spread of this global pandemic. This article focused on the effects of COVID-19 pandemic on potential safety issues with seafood products and their processing methods. Moreover, the potential impacts of coronavirus transmission through seafood on human health were evaluated. The role of authenticity, traceability, and antimicrobials from natural sources to preserve seafood and the possible interaction of functional foods on the human immune system are also discussed. Although seafood is not considered a principal vector of SARS-CoV-2 transmission, the possible infections through contaminated surfaces of such food products cannot be neglected. The positive effects of seafood consumption on possible immunity built up, and COVID-19 are also summarized.

Sea cucumber is rich in protein that can be used to prepare a potential derived bioactive peptide for antioxidant and protective effect against UV-B induced skin cell damage. This study aimed to optimize preparation of sea cucumber hydrolysate with both UV-B protective and antioxidant activities using three commercial enzymes using response surface methodology (RSM) with a face-centered central composite design (face- centered CCD). Hydrolysis time and concentration of enzyme effects on the degree of hydrolysis (DH), yield, antioxidant and UV-B protective activities of sea cucumber hydrolysates were determined. The optimum conditions for sea cucumber hydrolysis using papain (SCP), alcalase (SCA), or flavourzyme (SCF) were 3.6, 5.0, and 4.1% (w/w protein), respectively, and a hydrolysis time of 360 min. The resulting hydrolysates had a DH of 81-91%, yield of 13-14%, IC50 for DPPH radical scavenging activity of 0.3-4.1 mg/mL, FRAP of 0.5-0.6 mmol FeSO4/mL, and IC50 for ABTS radical scavenging activity of 1.3-1.6 mg/mL. The UV-B protective activity was reported as the HaCaT cell viability percentage after UV-B treatment. The SCP, SCA, and SCF hydrolysates showed 72.4, 74.5, and 71.3% cell viability, respectively. The concentration of hydrolysates with 80% survival of HaCaT cells was 0.21, 0.15 and 0.20 mg/mL for SCP, SCA and SCF, respectively. Thus, the SCP was selected for bioactive peptide isolation and characterization. The SCP contained hydrophilic and hydrophobic amino acids of 42.4 and 57.6%, respectively. The ultrafiltration and Sephadex G-25 gel filtration chromatography were done for peptide isolation from the SCP. Six potential peptides were identified using LC-MS/MS as Leu-Val-Asn-Glu-Leu-Thr-Glu-Phe-Ala-Gln (1163 Da), Leu-Val-Asn-Glu-Val-Thr-Glu-Phe-Ala-Gln (1149 Da), Phe-Val-Asp-Ser-Ser-Ala-Thr-Thr (826 Da), Phe-Asn-Asp-Leu-Gly-Ala-Trp (821 Da), Phe-Pro-Asp-Thr-Thr-Thr-Leu (793 Da), and Lys-Phe-Gly-Glu-Gly-Lys (664).

Abstract Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.

Steam cooking is a popular way of preparing fish and the end temperature plays a key role in the quality of the cooked fish. In this study, the lipid and protein oxidation, and the related changes in volatile compounds and in vitro digestibility of large-mouth bass ( Micropterus salmoides ) steam cooked to a core temperature of 45℃, 55℃, 65℃, 75℃, and 85℃ were investigated. Steaming caused a significant increase in the peroxide value (PV) and the thiobarbituric acid-reactive substances (TBARS) value, accompanied by the decreased proportion of unsaturated fatty acids like oleic acid and linoleic acid, which was related to the lipid oxidation and the increase in volatile aldehydes as indicated by the partial least squares analysis. The protein oxidation can be reflected by the significant decrease of total thiol groups, combined with the aggregation as shown in SDS-PAGE and the increase in particle size at pre-digestive phase. And the aggregation of proteins further caused the decreased digestibility of fish meat at the gastric phase, especially when the core temperature was above 75℃. Furthermore, steaming significantly decreased the aerobic count, and no coliform or generic E. coli was detected in steamed samples. Thus the core temperature of 65-75℃ was recommended for the consideration of food oxidation and microbial safety.

Problems with silver carp protein (SCP) include a strong fishy odor, low gel strength of SCP surimi, and susceptibility to gel degradation. The objective of this study was to improve the gel quality of SCP. The effects of the addition of native soy protein isolate (SPI) and SPI subjected to papain-restricted hydrolysis on the gel characteristics and structural features of SCP were studied. The β-sheet structures in SPI increased after papain treatment. SPI treated with papain was crosslinked with SCP using glutamine transaminase (TG) to form a composite gel. Compared with the control, the addition of modified SPI increased the hardness, springiness, chewiness, cohesiveness, and water-holding capacity (WHC) of the protein gel (p < 0.05). In particular, the effects were most significant when the degree of SPI hydrolysis (DH) was 0.5% (i.e., gel sample M-2). The molecular force results demonstrated that hydrogen bonding, disulfide bonding, and hydrophobic association are important molecular forces in gel formation. The addition of the modified SPI increases the number of hydrogen bonds and the disulfide bonds. Scanning electron microscopy (SEM) analysis showed that the papain modifications allowed the formation of a composite gel with a complex, continuous, and uniform gel structure. However, the control of the DH is important as additional enzymatic hydrolysis of SPI decreased TG crosslinking. Overall, modified SPI has the potential to improve SCP gel texture and WHC.

The quality and safety of sufu fermented using Mucor racemosa M2 was studied and compared with naturally fermented sufu. After 90 days post-fermentation, both naturally fermented and inoculated fermented sufu reached the maturity standard of sufu, and the degree of protein hydrolysis of natural sufu (WP/TP: 34% ± 1%; AAN/TN: 33% ± 1%) was slightly higher than that of the inoculated sufu (WP/TP: 28.2% ± 0.4%; AAN/TN: 27% ± 1%). The hardness and adhesiveness of inoculated sufu (Hadness: 1063 g ± 211 g; Adhesiveness: −80 g ± 47 g) were significantly greater than those of natural sufu (Hadness: 790 g ± 57 g; Adhesiveness: −23 g ± 28 g), and the internal structure of natural sufu was denser and more uniform than that of inoculated sufu. A total of 50 aroma compounds were detected in natural and inoculated sufu. The total number of bacterial colonies in naturally fermented sufu was significantly higher than that in inoculated sufu, and the pathogenic bacteria in both types of fermented sufu were lower than the limit of pathogenic bacteria required in fermented soybean products. The content of biogenic amines in sufu was determined by high performance liquid chromatography (HPLC), and the results showed that the content of biogenic amines (Putrescine, Cadaverine, Histamine, Tyramine, etc.) in naturally fermented sufu was significantly higher than that in inoculated fermented sufu. Especially the histamine content, after 90 days of fermentation, was found to be 64.95 ± 4.55 for inoculated fertilization and 44.24 ± 0.71 for natural fertilization. Overall, the quality of inoculated sufu was somewhat better than that of natural sufu, and the M2 strain can be used to ferment sufu.

Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase addition provides a simplified method to improve delivery of lipophilic drugs, where prolonged drug dissolution in the aqueous environment of the gastro-intestinal (GI) tract is known as the rate-limiting step rendering decreased drug absorption. Additionally, spontaneous emulsification has been reported as an innovative topical drug delivery system that enables successful crossing of mucus membranes as well as skin. The ease of formulation generated by the spontaneous emulsification technique itself is intriguing due to the simplified production procedure and unlimited upscaling possibilities. However, spontaneous emulsification depends solely on selecting excipients that complement each other in order to create a vehicle aimed at optimizing drug delivery. If excipients are not compatible or unable to spontaneously transpire into emulsions once exposed to mild agitation, no self-emulsification will be achieved. Therefore, the generalized view of excipients as inert bystanders facilitating delivery of an active compound cannot be accepted when selecting excipients needed to produce self-emulsifying drug delivery systems (SEDDSs). Hence, this review describes the excipients needed to generate dermal SEDDSs as well as self-double-emulsifying drug delivery systems (SDEDDSs); how to consider combinations that complement the incorporated drug(s); and an overview of using natural excipients as thickening agents and skin penetration enhancers.

Pleurotus eryngii (P. eryngii) is largely represented among consumed mushrooms. We conducted an investigation dealing with its antioxidant potential, the presence of essential trace elements and its contribution to the management of brain-related disorders. A bio-guided extraction revealed that one extract was highly effective on activation of the nuclear factor Nrf2, the regulator of the cellular resistance to oxidants. Its analysis revealed the presence of N-acetyltryptamine (NAT), a precursor of the neurotransmitters, melatonin and serotonin. Both extract and NAT, were found as competitive inhibitors of acetylcholinesterase. The essential trace elements analyses showed the presence of high amounts of zinc. RNA-seq technology confirmed upregulates expression of Nrf2 on HepG2 cells and revealed key genes involved in anticholesterolemic, antioxidant effects, cancer and brain disorders. Our study achieved a comprehensive strengthening of the nutritional health-benefit properties of P. eryngii largely used in folk medicines and open perspectives for investigation in food and medicine.

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March—June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if

Background Changes to the healthcare system due to COVID-19 have altered care delivery during birth and the postpartum period, a transitional time that requires intensive healthcare support and that is complicated by well-established health disparities. Our objective was to identify additional challenges to healthcare interactions that emerged for low-income postpartum individuals during the pandemic. Methods This is a qualitative investigation of low-income postpartum individuals enrolled in a trial of postpartum care, who gave birth in the United States in the first three months of the COVID-19 pandemic. Participants completed in-depth semi-structured interviews that addressed healthcare experiences during and after birth, both for in-person and telemedicine encounters. Transcripts were analyzed using the constant comparative method. Results Of 46 eligible individuals, 87% (N = 40) completed an interview, with 50% identifying as non-Hispanic Black and 38% as Hispanic. Challenges were organized into three domains: unanticipated changes in the birth experience, delayed care, and perceived disadvantages of telemedicine. Changes in the birth experience addressed uncertainty about COVID-19 status, COVID-19 testing, separation from newborn, and visitor restrictions. Delayed care themes addressed logistical challenges, postpartum care, health maintenance, and pediatric care. Participants reported multiple telemedicine-related challenges, including difficulty establishing rapport with providers. Conclusions Understanding the challenges experienced by low-income peripartum individuals as the COVID-19 pandemic evolves is critical to informing guidelines and diminishing inequities in healthcare delivery. Potential solutions that may mitigate limitations to care in the pandemic include emphasizing shared decision-making in care processes and developing communication strategies to improve telemedicine rapport.

Nrf2 is a major transcription factor that significantly regulates—directly or indirectly—more than 2000 genes. While many of these genes are involved in maintaining redox balance, others are involved in maintaining balance among metabolic pathways that are seemingly unrelated to oxidative stress. In the past 25 years, the number of factors involved in the activation, nuclear translocation, and deactivation of Nrf2 has continued to expand. The purpose of this review is to provide an overview of the remarkable complexity of the tortuous sequence of stop-and-go signals that not only regulate expression or repression, but may also modify transcriptional intensity as well as the specificity of promoter recognition, allowing fluidity of its gene expression profile depending on the various structural modifications the transcription factor encounters on its journey to the DNA. At present, more than 45 control points have been identified, many of which represent sites of action of the so-called Nrf2 activators. The complexity of the pathway and the synergistic interplay among combinations of control points help to explain the potential advantages seen with phytochemical compositions that simultaneously target multiple control points, compared to the traditional pharmaceutical paradigm of “one-drug, one-target”.

This study aimed to investigate the properties of acidic whey tofu gelatin generated from two acidic whey coagulants by pure fermentation of Lactiplantibacillus paracasei and L. plantarum, as well as the characteristics of acidic whey tofu. The optimal holding temperature and the amount of coagulants added were determined based on the pH, water-holding capacity, texture, microstructure, and rheological properties of tofu gelation. Then, the differences in quality between tofu produced by pure bacterial fermentation and by natural fermentation were investigated under optimal tofu gelatin preparation conditions. The tofu gelatin presented the best texture at 37 °C with a 10% addition of coagulants fermented by both L. paracasei and L. plantarum. Under these conditions, the coagulant produced by the fermentation of L. plantarum resulted in a shorter formation time and stronger tofu gelatin compared with that produced from L. paracasei. Tofu produced by the fermentation of L. paracasei had higher pH, less hardness, and a rougher network structure, whereas tofu produced by the fermentation of L. plantarum was closer to tofu produced by natural fermentation in terms of pH, texture, rheology, and microstructure.

Our previous work identified human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) as a putative driver of LPS-induced NF-κB signaling in humans in vivo. While HIVEP1 is known to interact with NF-ĸB binding DNA motifs, its function in mammalian cells is unknown. We report increased HIVEP1 mRNA expression in monocytes from patients with sepsis and monocytes stimulated by Toll-like receptor agonists and bacteria. In complementary overexpression and gene deletion experiments HIVEP1 was shown to inhibit NF-ĸB activity and induction of NF-ĸB responsive genes. RNA sequencing demonstrated profound transcriptomic changes in HIVEP1 deficient monocytic cells and transcription factor binding site analysis showed enrichment for κB site regions. HIVEP1 bound to the promoter regions of NF-ĸB responsive genes. Inhibition of cytokine production by HIVEP1 was confirmed in LPS-stimulated murine Hivep1-/- macrophages and HIVEP1 knockdown zebrafish exposed to the common sepsis pathogen Streptococcus pneumoniae. These results identify HIVEP1 as a negative regulator of NF-κB in monocytes/macrophages that inhibits proinflammatory reactions in response to bacterial agonists in vitro and in vivo.

Viral infections may cause serious human diseases. For instance, the recent appearance of the novel virus, SARS-CoV-2, causing COVID-19, has spread globally and is a serious public health concern. The consumption of healthy, proper, functional, and nutrient-rich foods has an important role in enhancing an individual's immune system and preventing viral infections. Several polysaccharides from natural sources such as algae, bacteria, and fungi have been considered as generally recognized as safe (GRAS) by the US Food and Drug Administration. They are safe, low-toxicity, biodegradable, and have biological activities. In this review, the bioactive polysaccharides derived from various microorganisms, including bacteria, fungi, and algae were evaluated. Antiviral mechanisms of these polysaccharides were discussed. Finally, the potential use of microbial and algal polysaccharides as an antiviral and immune boosting strategy was addressed. The microbial polysaccharides exhibited several bioactivities, including antioxidant, anti-inflammatory, antimicrobial, antitumor, and immunomodulatory activities. Some microbes are able to produce sulfated polysaccharides, which are well-known to exert a board spectrum of biological activities, especially antiviral properties. Microbial polysaccharide can inhibit various viruses using different mechanisms. Furthermore, these microbial polysaccharides are also able to modulate immune responses to prevent and/or inhibit virus infections. There are many molecular factors influencing their bioactivities, e.g., functional groups, conformations, compositions, and molecular weight. At this stage of development, microbial polysaccharides will be used as adjuvants, nutrient supplements, and for drug delivery to prevent several virus infections, especially SARS-CoV-2 infection.

There is a need to develop new ways of protecting plants against aphid attack. Here, we investigated the effect of a plant defence activator, cis-jasmone (CJ), in a range of cultivars of Brassica napus, Brassica rapa and Brassica oleracea. Plants were sprayed with cis-jasmone or blank formulation and then tested with peach potato aphids (Myzus persicae Sulzer) (Hemiptera: Aphididae) and their parasitoid Diaeretiella rapae (M'Intosh) (Hymenoptera: Braconidae). CJ treated plants had significantly lower aphid settlement than control plants in a settlement bioassay. Conversely, in a foraging bioassay, D. rapae parasitoids spent a significantly longer time foraging on CJ treated plants. Our results reveal that CJ treatment makes plants less attractive to and less suitable for M. persicae but more attractive to D. rapae in a range of brassica cultivars. It is likely that these effects are due to changes in volatile emission indicating activation of defence and presence of conspecific competitors to aphids but presence of prey to parasitoids. Increases in volatile emission were found in CJ induced plants but varied with genotype. Among the synthetic volatile compounds that were induced in the headspace of CJ treated brassica cultivars, methyl isothiocyanate, methyl salicylate and cis-jasmone were most repellent to aphids. These results build on earlier studies in Arabidopsis and show that tritrophic interactions are influenced by CJ in a wide range of brassica germplasm. The implication is that CJ is a promising treatment that could be used in brassica crops as part of an integrated pest management system.

Background Bacterial intestinal communities interact with the immune system and may contribute to protection against community-acquired pneumonia (CAP). Intestinal viruses are closely integrated with these bacterial communities, yet the composition and clinical significance of these communities in CAP patients are unknown. The aims of this exploratory study were to characterise the composition of the rectal bacteriome and virome at hospital admission for CAP, and to determine if microbiota signatures correlate with clinical outcomes.Methods We performed a prospective observational cohort study in CAP patients, admitted to a university or community hospital in the Netherlands between October 2016 and July 2018, and controls. Rectal bacteriome and virome composition were characterised using 16S ribosomal RNA gene sequencing and virus discovery next-generation sequencing, respectively. Unsupervised multi-omics factor analysis was used to assess the co-variation of bacterial and viral communities, which served as primary predictor. The clinical outcomes of interest were the time to clinical stability and the length of hospital stay.Findings 64 patients and 38 controls were analysed. Rectal bacterial alpha (p = 0•0015) and beta diversity (r2=0•023, p = 0•004) of CAP patients differed from controls. Bacterial and viral microbiota signatures correlated with the time to clinical stability (hazard ratio 0•43, 95% confidence interval 0•20–0•93, p = 0•032) and the length of hospital stay (hazard ratio 0•37, 95% confidence interval 0•17–0•81, p = 0•012), although only the latter remained significant following p-value adjustment for examining multiple candidate cut-points (p = 0•12 and p = 0•046, respectively).Interpretation This exploratory study provides preliminary evidence that intestinal bacteriome and virome signatures could be linked with clinical outcomes in CAP. Such exploratory data, when validated in independent cohorts, could inform the development of a microbiota-based diagnostic panel used to predict clinical outcomes in CAP.Funding Netherlands Organization for Scientific Research and Netherlands Organization for Health Research and Development.

Abstract Background Men with metastatic castrate-resistant prostate cancer can experience an array of treatment-related side effects. Accumulating evidence suggests exercise may alleviate some of these adversities and assist in disease management. However, empirical evidence in advanced prostate cancer patients remains limited. The purpose of this study is to determine whether men with metastatic prostate cancer, who are ineligible for high-intensity exercise, can partake in a home-based, moderate-intensity exercise program and the impact of doing so on quality of life and physical fitness parameters. Methods Thirty men with adenocarcinoma of the prostate and progressive systemic, metastatic disease will be recruited. Clinicians will screen patients against inclusion criteria to determine eligibility. All men enrolled will be prescribed a tailored, home-based, moderate-intensity exercise intervention consisting of aerobic and strengthening components for 12 weeks. Patients will receive supplementary education materials and weekly behavioural change consultations throughout the intervention. The primary outcome will be the feasibility of delivering such an intervention in men with metastatic disease. Secondary endpoints including skeletal events will be monitored for safety, as will the feasibility of patient-reported outcome measures and the sampling time points, generating data pertaining to completion rates and potential effect in future trials. General physical fitness will be assessed during these visits, using timed sit-to-stand testing and a 6-min walking test. Prior to each visit, objective physical activity levels will be captured for 7 days using an accelerometer, to determine the feasibility of this technology and the quality of data obtained. In parallel with the feasibility aspects of the trial, changes compared to baseline will be reported. Direct regular contact will also serve as a feedback loop, should any issues arise. This study has received ethical approval from the Office for Research Ethics Committees Northern Ireland. Conclusions This study aims to determine the potential utility of a home-based exercise intervention in managing side effects associated with advanced prostate cancer and its treatment. This feasibility trial will inform the design and implementation of a larger randomised control trial to determine the efficacy of moderate aerobic and strengthening exercise as an adjuvant therapy in men with metastatic prostate cancer. Collecting such evidence provides further support for exercise in this paradigm and potential for its inclusion as a low-toxicity therapy in standard cancer care, in the longer term. Trial registration ClinicalTrials.gov, NCT03658486 Trial sponsor: Queen’s University Belfast (Reference: B18/15). Contact: Dr. Paula Tighe, Research and Enterprise, Queen’s University Belfast. Telephone: 02890 973,296. Email: p.tighe@qub.ac.uk. The sponsor reviewed the protocol and ethical application prior to submission. Protocol issue: Version 1 (18th May 2018). Authors: MB, MM, SJ and GP.

The liver parenchyma consists of several cell types, but the origin of this tissue in humans is unclear. Here, the authors perform single cell RNA sequencing of human fetal and adult liver to identify a hepatobiliary hybrid progenitor population of cells, which have a similar gene signature to mouse oval cells.