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Michael Weekes

and 11 more

Nick K. Jones1,2*, Lucy Rivett1,2*, Chris Workman3, Mark Ferris3, Ashley Shaw1, Cambridge COVID-19 Collaboration1,4, Paul J. Lehner1,4, Rob Howes5, Giles Wright3, Nicholas J. Matheson1,4,6¶, Michael P. Weekes1,7¶1 Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK2 Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, UK3 Occupational Health and Wellbeing, Cambridge Biomedical Campus, Cambridge, UK4 Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK5 Cambridge COVID-19 Testing Centre and AstraZeneca, Anne Mclaren Building, Cambridge, UK6 NHS Blood and Transplant, Cambridge, UK7 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK*Joint first authorship¶Joint last authorshipCorrespondence: [email protected] UK has initiated mass COVID-19 immunisation, with healthcare workers (HCWs) given early priority because of the potential for workplace exposure and risk of onward transmission to patients. The UK’s Joint Committee on Vaccination and Immunisation has recommended maximising the number of people vaccinated with first doses at the expense of early booster vaccinations, based on single dose efficacy against symptomatic COVID-19 disease.1-3At the time of writing, three COVID-19 vaccines have been granted emergency use authorisation in the UK, including the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech). A vital outstanding question is whether this vaccine prevents or promotes asymptomatic SARS-CoV-2 infection, rather than symptomatic COVID-19 disease, because sub-clinical infection following vaccination could continue to drive transmission. This is especially important because many UK HCWs have received this vaccine, and nosocomial COVID-19 infection has been a persistent problem.Through the implementation of a 24 h-turnaround PCR-based comprehensive HCW screening programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT), we previously demonstrated the frequent presence of pauci- and asymptomatic infection amongst HCWs during the UK’s first wave of the COVID-19 pandemic.4 Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and cycle threshold (Ct) values in the asymptomatic arm of our programme, which now offers weekly screening to all staff.Vaccination of HCWs at CUHNFT began on 8th December 2020, with mass vaccination from 8th January 2021. Here, we analyse data from the two weeks spanning 18thto 31st January 2021, during which: (a) the prevalence of COVID-19 amongst HCWs remained approximately constant; and (b) we screened comparable numbers of vaccinated and unvaccinated HCWs. Over this period, 4,408 (week 1) and 4,411 (week 2) PCR tests were performed from individuals reporting well to work. We stratified HCWs <12 days or > 12 days post-vaccination because this was the point at which protection against symptomatic infection began to appear in phase III clinical trial.226/3,252 (0·80%) tests from unvaccinated HCWs were positive (Ct<36), compared to 13/3,535 (0·37%) from HCWs <12 days post-vaccination and 4/1,989 (0·20%) tests from HCWs ≥12 days post-vaccination (p=0·023 and p=0·004, respectively; Fisher’s exact test, Figure). This suggests a four-fold decrease in the risk of asymptomatic SARS-CoV-2 infection amongst HCWs ≥12 days post-vaccination, compared to unvaccinated HCWs, with an intermediate effect amongst HCWs <12 days post-vaccination.A marked reduction in infections was also seen when analyses were repeated with: (a) inclusion of HCWs testing positive through both the symptomatic and asymptomatic arms of the programme (56/3,282 (1·71%) unvaccinated vs 8/1,997 (0·40%) ≥12 days post-vaccination, 4·3-fold reduction, p=0·00001); (b) inclusion of PCR tests which were positive at the limit of detection (Ct>36, 42/3,268 (1·29%) vs 15/2,000 (0·75%), 1·7-fold reduction, p=0·075); and (c) extension of the period of analysis to include six weeks from December 28th to February 7th 2021 (113/14,083 (0·80%) vs 5/4,872 (0·10%), 7·8-fold reduction, p=1x10-9). In addition, the median Ct value of positive tests showed a non-significant trend towards increase between unvaccinated HCWs and HCWs > 12 days post-vaccination (23·3 to 30·3, Figure), suggesting that samples from vaccinated individuals had lower viral loads.We therefore provide real-world evidence for a high level of protection against asymptomatic SARS-CoV-2 infection after a single dose of BNT162b2 vaccine, at a time of predominant transmission of the UK COVID-19 variant of concern 202012/01 (lineage B.1.1.7), and amongst a population with a relatively low frequency of prior infection (7.2% antibody positive).5This work was funded by a Wellcome Senior Clinical Research Fellowship to MPW (108070/Z/15/Z), a Wellcome Principal Research Fellowship to PJL (210688/Z/18/Z), and an MRC Clinician Scientist Fellowship (MR/P008801/1) and NHSBT workpackage (WPA15-02) to NJM. Funding was also received from Addenbrooke’s Charitable Trust and the Cambridge Biomedical Research Centre. We also acknowledge contributions from all staff at CUHNFT Occupational Health and Wellbeing and the Cambridge COVID-19 Testing Centre.

Guangming Wang

and 4 more

Tam Hunt

and 1 more

Tam Hunt [1], Jonathan SchoolerUniversity of California Santa Barbara Synchronization, harmonization, vibrations, or simply resonance in its most general sense seems to have an integral relationship with consciousness itself. One of the possible “neural correlates of consciousness” in mammalian brains is a combination of gamma, beta and theta synchrony. More broadly, we see similar kinds of resonance patterns in living and non-living structures of many types. What clues can resonance provide about the nature of consciousness more generally? This paper provides an overview of resonating structures in the fields of neuroscience, biology and physics and attempts to coalesce these data into a solution to what we see as the “easy part” of the Hard Problem, which is generally known as the “combination problem” or the “binding problem.” The combination problem asks: how do micro-conscious entities combine into a higher-level macro-consciousness? The proposed solution in the context of mammalian consciousness suggests that a shared resonance is what allows different parts of the brain to achieve a phase transition in the speed and bandwidth of information flows between the constituent parts. This phase transition allows for richer varieties of consciousness to arise, with the character and content of that consciousness in each moment determined by the particular set of constituent neurons. We also offer more general insights into the ontology of consciousness and suggest that consciousness manifests as a relatively smooth continuum of increasing richness in all physical processes, distinguishing our view from emergentist materialism. We refer to this approach as a (general) resonance theory of consciousness and offer some responses to Chalmers’ questions about the different kinds of “combination problem.”  At the heart of the universe is a steady, insistent beat: the sound of cycles in sync…. [T]hese feats of synchrony occur spontaneously, almost as if nature has an eerie yearning for order. Steven Strogatz, Sync: How Order Emerges From Chaos in the Universe, Nature and Daily Life (2003) If you want to find the secrets of the universe, think in terms of energy, frequency and vibration.Nikola Tesla (1942) I.               Introduction Is there an “easy part” and a “hard part” to the Hard Problem of consciousness? In this paper, we suggest that there is. The harder part is arriving at a philosophical position with respect to the relationship of matter and mind. This paper is about the “easy part” of the Hard Problem but we address the “hard part” briefly in this introduction.  We have both arrived, after much deliberation, at the position of panpsychism or panexperientialism (all matter has at least some associated mind/experience and vice versa). This is the view that all things and processes have both mental and physical aspects. Matter and mind are two sides of the same coin.  Panpsychism is one of many possible approaches that addresses the “hard part” of the Hard Problem. We adopt this position for all the reasons various authors have listed (Chalmers 1996, Griffin 1997, Hunt 2011, Goff 2017). This first step is particularly powerful if we adopt the Whiteheadian version of panpsychism (Whitehead 1929).  Reaching a position on this fundamental question of how mind relates to matter must be based on a “weight of plausibility” approach, rather than on definitive evidence, because establishing definitive evidence with respect to the presence of mind/experience is difficult. We must generally rely on examining various “behavioral correlates of consciousness” in judging whether entities other than ourselves are conscious – even with respect to other humans—since the only consciousness we can know with certainty is our own. Positing that matter and mind are two sides of the same coin explains the problem of consciousness insofar as it avoids the problems of emergence because under this approach consciousness doesn’t emerge. Consciousness is, rather, always present, at some level, even in the simplest of processes, but it “complexifies” as matter complexifies, and vice versa. Consciousness starts very simple and becomes more complex and rich under the right conditions, which in our proposed framework rely on resonance mechanisms. Matter and mind are two sides of the coin. Neither is primary; they are coequal.  We acknowledge the challenges of adopting this perspective, but encourage readers to consider the many compelling reasons to consider it that are reviewed elsewhere (Chalmers 1996, Griffin 1998, Hunt 2011, Goff 2017, Schooler, Schooler, & Hunt, 2011; Schooler, 2015).  Taking a position on the overarching ontology is the first step in addressing the Hard Problem. But this leads to the related questions: at what level of organization does consciousness reside in any particular process? Is a rock conscious? A chair? An ant? A bacterium? Or are only the smaller constituents, such as atoms or molecules, of these entities conscious? And if there is some degree of consciousness even in atoms and molecules, as panpsychism suggests (albeit of a very rudimentary nature, an important point to remember), how do these micro-conscious entities combine into the higher-level and obvious consciousness we witness in entities like humans and other mammals?  This set of questions is known as the “combination problem,” another now-classic problem in the philosophy of mind, and is what we describe here as the “easy part” of the Hard Problem. Our characterization of this part of the problem as “easy”[2] is, of course, more than a little tongue in cheek. The authors have discussed frequently with each other what part of the Hard Problem should be labeled the easier part and which the harder part. Regardless of the labels we choose, however, this paper focuses on our suggested solution to the combination problem.  Various solutions to the combination problem have been proposed but none have gained widespread acceptance. This paper further elaborates a proposed solution to the combination problem that we first described in Hunt 2011 and Schooler, Hunt, and Schooler 2011. The proposed solution rests on the idea of resonance, a shared vibratory frequency, which can also be called synchrony or field coherence. We will generally use resonance and “sync,” short for synchrony, interchangeably in this paper. We describe the approach as a general resonance theory of consciousness or just “general resonance theory” (GRT). GRT is a field theory of consciousness wherein the various specific fields associated with matter and energy are the seat of conscious awareness.  A summary of our approach appears in Appendix 1.  All things in our universe are constantly in motion, in process. Even objects that appear to be stationary are in fact vibrating, oscillating, resonating, at specific frequencies. So all things are actually processes. Resonance is a specific type of motion, characterized by synchronized oscillation between two states.  An interesting phenomenon occurs when different vibrating processes come into proximity: they will often start vibrating together at the same frequency. They “sync up,” sometimes in ways that can seem mysterious, and allow for richer and faster information and energy flows (Figure 1 offers a schematic). Examining this phenomenon leads to potentially deep insights about the nature of consciousness in both the human/mammalian context but also at a deeper ontological level.

Susanne Schilling*^

and 9 more

Jessica mead

and 6 more

The construct of wellbeing has been criticised as a neoliberal construction of western individualism that ignores wider systemic issues including increasing burden of chronic disease, widening inequality, concerns over environmental degradation and anthropogenic climate change. While these criticisms overlook recent developments, there remains a need for biopsychosocial models that extend theoretical grounding beyond individual wellbeing, incorporating overlapping contextual issues relating to community and environment. Our first GENIAL model \cite{Kemp_2017} provided a more expansive view of pathways to longevity in the context of individual health and wellbeing, emphasising bidirectional links to positive social ties and the impact of sociocultural factors. In this paper, we build on these ideas and propose GENIAL 2.0, focusing on intersecting individual-community-environmental contributions to health and wellbeing, and laying an evidence-based, theoretical framework on which future research and innovative therapeutic innovations could be based. We suggest that our transdisciplinary model of wellbeing - focusing on individual, community and environmental contributions to personal wellbeing - will help to move the research field forward. In reconceptualising wellbeing, GENIAL 2.0 bridges the gap between psychological science and population health health systems, and presents opportunities for enhancing the health and wellbeing of people living with chronic conditions. Implications for future generations including the very survival of our species are discussed.  

Mark Ferris

and 14 more

IntroductionConsistent with World Health Organization (WHO) advice [1], UK Infection Protection Control guidance recommends that healthcare workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) should use fluid resistant surgical masks type IIR (FRSMs) as respiratory protective equipment (RPE), unless aerosol generating procedures (AGPs) are being undertaken or are likely, when a filtering face piece 3 (FFP3) respirator should be used [2]. In a recent update, an FFP3 respirator is recommended if “an unacceptable risk of transmission remains following rigorous application of the hierarchy of control” [3]. Conversely, guidance from the Centers for Disease Control and Prevention (CDC) recommends that HCWs caring for patients with COVID-19 should use an N95 or higher level respirator [4]. WHO guidance suggests that a respirator, such as FFP3, may be used for HCWs in the absence of AGPs if availability or cost is not an issue [1].A recent systematic review undertaken for PHE concluded that: “patients with SARS-CoV-2 infection who are breathing, talking or coughing generate both respiratory droplets and aerosols, but FRSM (and where required, eye protection) are considered to provide adequate staff protection” [5]. Nevertheless, FFP3 respirators are more effective in preventing aerosol transmission than FRSMs, and observational data suggests that they may improve protection for HCWs [6]. It has therefore been suggested that respirators should be considered as a means of affording the best available protection [7], and some organisations have decided to provide FFP3 (or equivalent) respirators to HCWs caring for COVID-19 patients, despite a lack of mandate from local or national guidelines [8].Data from the HCW testing programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT) during the first wave of the UK severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic indicated a higher incidence of infection amongst HCWs caring for patients with COVID-19, compared with those who did not [9]. Subsequent studies have confirmed this observation [10, 11]. This disparity persisted at CUHNFT in December 2020, despite control measures consistent with PHE guidance and audits indicating good compliance. The CUHNFT infection control committee therefore implemented a change of RPE for staff on “red” (COVID-19) wards from FRSMs to FFP3 respirators. In this study, we analyse the incidence of SARS-CoV-2 infection in HCWs before and after this transition.

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Most recent documents

Luis Garcia-Marcos

and 10 more

Objectives To characterise the epidemiology of atopic eczema in adolescents from Kosovo, an area of very low prevalence of the condition and to know whether the same factors are associated to eczema with or without comorbid wheezing symptoms. Methods The cross-sectional survey Global Asthma Network validated questionnaire was self-completed by adolescents 13-14 years of age in the school setting from the main cities of Kosovo: Ferizaj, Gjakova, Gjilan, Peja, Prishtina and Prizren. Atopic eczema symptoms and diagnosis was put in relation with the environmental questionnaire which included questions on smoking; pet ownership; paracetamol use, truck traffic; siblings; time spent using screens or watching television; and exercise. Additionally, height and weight were measured at school. Results The prevalence of eczema symptoms ranged from 2.2% in Ferizaj to 5.5% in Gjakova. Severe symptoms were <1% in all cities. Eczema ever ranged from 3.0% in Ferizaj to 6.4% in Prizren. Factors significantly associated to the prevalence of current eczema symptoms in the metanalysis were male sex (pooled aOR 0.50; 95%CI 0.37-0.66); exercise (pooled aOR 2.79; 95%CI 1.89-4.10); and paracetamol intake (pooled 1.86; 95%CI 1.32-2.64). The corresponding figures for eczema ever were: 0.68 95%CI 0.44-1.06; 2.07 95%CI 1.48-2.90; and 1.19 95%CI 0.88-1.60. The associations tended to be higher in the subpopulation with eczema and wheeze comorbidity. Conclusions The prevalence of atopic eczema is very low in Kosovo and is associated to female sex, exercise, and paracetamol intake. Those associations are higher when eczema and wheezing are comorbid conditions.

Yifei Xue

and 10 more

Objective:Population pharmacokinetics analysis explored the pharmacokinetics of anlotinib in children with soft tissue sarcomas (STS) and identified the optimal dose for children across various age brackets. Method:From 2021 to 2023, a single dose of anlotinib (4.62 mg/m2) was orally administered in 16 children with advanced STS in 8 days. Anlotinib plasma concentration was evaluated by LC-MS/MS. Pharmacokinetic models were developed using nonlinear mixed-effects modelling. The effect of predefined covariates on pharmacokinetic parameters was assessed. Results:Totally 128 samples from 16 children (aged 5-14) were collected for pop-PK analysis. The two-compartment model was most consistent with the data of oral anlotinib in pediatrics with advanced STS, and the relevant parameters were: Ka (h-1) 0.419; Vc/F (L) 760; Q (L∙h-1) 21.2; Vp/F (L) 547. Covariate screening showed that the clearance of anlotinib gradually increased with age in a sigmoidal relationship, the maximum CL/F was 15.7L∙h-1, and age of median clearance (Age50) was 6.84 years; the Vc/F increased linearly with BSA. Dose of 8 mg anlotinib for children aged 5-7, and 10 mg or 12 mg for children aged 8-10 would be expected to lead to a similar exposure of anlotinib compared with an adult patient receiving 12 mg. Conclusion:The population pharmacokinetics of orally administrated anlotinib were evaluated in pediatric advanced STS patients. BSA and age were significant physiologic factors on PK. A simulation of 8 mg anlotinib in children aged 5-7, 10 mg or 12 mg in 8-10 and 12 mg for children over 11 would get similar exposure of adults receiving 12mg.

Shih-Chin Cheng

and 7 more

Background IL-4 and IL-13, pivotal components of type 2 immunity, have been implicated in inducing trained immunity in myeloid cells. However, the precise inflammatory response of monocytes in individuals with type 2 immune disorders remains uncertain. Objective To investigate the nuanced inflammatory response of monocytes in patients with type 2 immune disorders, specifically atopic dermatitis and urticaria, upon exposure to LPS stimulation. Methods We collected peripheral blood mononuclear cells (PBMCs) from patients diagnosed with atopic dermatitis and urticaria. Monocytes were isolated from PBMCs and subjected to targeted LPS stimulation. RNA extraction followed by RNA-seq and ATAC-seq analyses were conducted to elucidate molecular responses. Results Monocytes from patients with type 2 immune disorders exhibited an augmented inflammatory response upon LPS stimulation. RNA-seq analysis demonstrated significant upregulation of inflammatory cytokines, including IL-6, IL-12, and IL-1b. Moreover, there was a conspicuous enrichment of signaling pathways associated with inflammation. ATAC sequencing revealed heightened chromatin accessibility in patient monocytes, particularly in the promoter regions of inflammatory genes. Conclusion Our findings unveil an intensified pro-inflammatory response in monocytes following LPS stimulation in type 2 immune disorders such as atopic dermatitis and urticaria. The comprehensive RNA and chromatin analyses underscore the pivotal role of type 2 immune responses in shaping the epigenetically defined inflammatory phenotypes of peripheral monocytes.

Aida B. Moreira

and 4 more

Super duplex stainless steels (SDSS) have an ideally dual-phase microstructure composed of austenite and ferrite. However, due to variations in cooling rate, secondary phases (SP), such as sigma, may arise, jeopardising the fatigue performance. This work investigates the correlation between macroscale fatigue behaviour and the multiphase microstructure in SDSS. Fatigue tests were conducted using miniature specimens representative of three regions of a cast C-Ring with different cooling rates, meaning distinct SP amounts. A numerical model was proposed to assess the fatigue test parameters. SEM and EBSD techniques were used to quantify the SP and analyse the fatigue-crack propagation, complemented by hardness and tensile test results. Regression models were developed to correlate the percentage of SP, the fatigue resistance and the number of cycles to failure, and to predict the microstructural stress concentrations from the amount of SP. In addition, a methodology is proposed for predicting S-N curves as a function of the amount of SP. The results show a high correspondence in the increase of the percentage of SP with the decrease in fatigue life. The fatigue strength, for a given number of cycles to failure, tends to decrease linearly with increasing the SP. The microstructural stress concentration factor tends to increase with increasing SP. The research described in this manuscript contributes to further knowledge on predicting the behaviour of SDSS under different cyclic conditions, which can be valuable for optimizing design and performance in various applications.

Mingming Li

and 12 more

Background: Adverse effects resulting from Capecitabine-based chemotherapy pose a significant concern in clinical practice. While the pharmacokinetics (PK) approach has been commonly used to investigate the toxicity of Capecitabine, its predictive ability remains limited. This study aims to assess whether pre-chemotherapy endogenous plasma metabolome can offer improved predictive values for Capecitabine chemotherapy-related adverse events (CRAEs). Methods: Plasma samples were collected from colorectal cancer patients at different time points: 0 hours (before), and 1, 2.5, 4 hours after oral Capecitabine administration, to assess individual variations in exposure levels of Capecitabine and its metabolites. Additionally, the endogenous metabolome profile was analyzed using UHPLC-MS/MS and UHPLC/Q-TOF-MS. Results: Capecitabine and its metabolites can predict two CRAEs, with 5-FU, 5’-DFCR, and FUH2 exposures being associated with diarrhea and thrombocytopenia, respectively. In contrast, identified plasma engougenous biomarker metabolites can predict all seven observed CRAEs. These CRAE-related endogenous plasma metabolites are involved in various physiological functions, including cell proliferation, maintenance, and inflammation. Pre-chemotherapy endogenous plasma metabolites established superior predictive performance for CRAEs (AUROC values ranging from 0.834 to 0.984) compared to conventional drug exposure (AUROC values ranging from 0.737 to 0.773). Additionally, the endogenous plasma metabolome demonstrated a strong correlation with Capecitabine and its metabolite exposures. Conclusions: Our study demonstrates that pre-chemotherapy endogenous plasma metabolome serve as superior biomarkers for predicting Capecitabine-related adverse effects, surpassing the value of exposures to Capecitabine and its metabolites. This finding holds significant potential in guiding personalized medicine approaches.

Samitha Kottage

and 3 more

Dry fractionation is an environmentally friendly and cost-effective method to separate protein fractions. While most research has focused on the structure and functional properties of pea protein isolates (PPI), the information on dry fractionated pea protein (DFPP) is limited. This study compared DFPP (protein content (PC)-50.7%, insoluble fiber-17%), to PPI (PC-80.1%, insoluble fiber-8.33%), in terms of the protein structure, solubility, and heat-induced gelation. SDS-Page, size-exclusive chromatographic, and Fourier-transform infrared spectrophotometer analysis indicated that DFPP contained the major protein components in pea, and their native structures were well maintained. Whereas for PPI, some proteins were lost during wet extraction, and partial protein unfolding and aggregation were observed. At neutral pH, DFPP showed significantly higher solubility (44.64±0.55%) than PPI (12.09±1.42%). Interestingly, DFPP showed good gelling capacity as reflected by lower gelling concentration and higher gel mechanical strength and elasticity compared to those made from PPI. The DFPP gels were twice higher in mechanical strength (7.71±0.21kPa) than that prepared from PPI at pH 7. Strong gels were also obtained for DFPP at pH 5. The gel morphology revealed phase separation between protein and polysaccharides by heating, with stick-shaped fiber (10-25μm) dispersed in the continuous protein networks. Eventually, the polysaccharides including fiber and starch helped strengthen the gel network by acting as fillers. This knowledge will help to expand the applications of DFPP as a gelling ingredient in food formulations, but also allow industry to benefit from the dietary fiber co-exist in the protein to develop healthier food products using a holistic approach.

Yiwen Ren

and 4 more

Background:With the mounting number of intrauterine operations, the incidence of intrauterine adhesion continues to rise. However, the specific pathogenesis of intrauterine adhesion has not been clear and there is no fundamental treatment so far. Objective:IUA is an endometrial fibrosis illness that gravely jeopardizes the reproductive health of women of reproductive age. We elucidated the pathogenesis of IUA at the protein level to provide a more effective research basis for diagnosis and treatment. Methods: This study collected 15 endometrial tissue samples and divided them into three comparison groups (Adhesion/Control group, Endometrium/Adhesion group, and Endometrium/Control group). Label-free quantitative proteomics was used to identify differentially expressed proteins and performed a comprehensive bioinformatics analysis. The research was followed by a quantitative analysis of selected target proteins using a parallel reaction monitoring method. Results: 1328, 290, and 1335 differential proteins were found in each comparison group. Many features of the differential proteins were also identified by GO enrichment analysis and KEGG pathways analysis. Parallel reaction monitoring analysis was performed to quantify 14 target proteins (PGM5, CAMK2G, ABHD6, MYLK, SYNPO2, LTF, PTPN11, TGF-β1, SLC4A1, PROS1, IRAG1, ADIPOQ, HLA-DRB3, COQ6). Among them, TGF-β1 was previously reported as a significant protein in intrauterine adhesion, while other proteins were newly discovered. Conclusions: These proteins are anticipated to develop as biomarkers for intrauterine adhesion and have a specific role in diagnosis and therapy.

Zaixiang Lou

and 4 more

The study focused on the impact and action mechanism of different organic selenium products on the bioactivity of two strains of Lactobacillus paracasei. The growth, antioxidant activity, extracellular polysaccharide secretion, quorum sensing and biofilm formation of the strains before and after the addition of organic selenium crude products and three organic selenium standard were evaluated. The results showed that the addition of crude organic selenium had a promoting effect on the growth, antioxidant activity, extracellular polysaccharide, biofilm formation, and AI-2 activity of the strain. The organic selenium standards had a regulatory effect (positive and negative) on biofilm formation and the activity of the QS signal molecule AI-2 in the strain. L-selenocysteine had the strongest regulatory effect, with maximum GIM1.80 biofilm formation when it reached a critical concentration of 0.4 μg/ml; L-selenomethionine resulted in the highest activity of the signal molecule AI-2 of GDMCC1.155, when it reached a critical concentration of 0.4 μg/ml. The results of scanning electron microscopy demonstrated that organic selenium effectively improved the morphology and structure of the bacterial cells of the two strains. Molecular docking revealed that the mechanism by which organic selenium regulates quorum sensing in Lactobacillus was achieved by binding two crucial receptor proteins (histidine protein kinase HKP and periplasmic binding protein LuxP) from specific sites. It provides a new alternative (organic selenium) for regulating the viability and beneficial activity of Lactobacillus paracasei. Significance statement: The study found that organic selenium can both positively and negatively regulate quorum sensing and biofilm formation of Lactobacillus, and the critical concentrations have also been obtained. Meanwhile, it was found that organic selenium can promote the growth, antioxidant activity, and biofilm formation of Lactobacillus by activating quorum sensing, so as to better exert its probiotic properties. Furthermore, the regulating mechanism of organic selenium on the activity of Lactobacillus was revealed. This study provides a new alternative for regulating and stimulating the beneficial activity of probiotics.

Abdulla Badawy

and 1 more

It is almost universally thought that modulation of immune function by tryptophan (Trp) metabolites involves activation of the aryl hydrocarbon receptor (AhR) mainly by kynurenine (Kyn), based on enhanced expression of cytochrome P-450 enzymes and their increased activities in cell systems and in vivo. However, DiNatale et al. (Toxicol. Sci. 2010; 115: 89-97) reported the failure of Kyn at 10 M to activate the AhR, whereas a similar concentration of kynurenic acid (KA) was effective. The recent study by Solvay et al (J Immunother Cancer 2023; 11: e006728) called into question the direct link between Kyn and the AhR and demonstrated down regulation of the AhR by Trp. In the present study, we have performed for the first time molecular docking in silico to the human AhR of the above and a range of other Trp metabolites produced in the various degradative pathways and by gut microbiota. We demonstrate that, of 29 Trp metabolites, only Kyn and 3-hydroxykynurenine fail to dock to the AhR and propose that AhR activation by Kyn is an indirect effect mediated by KA. The strongest docking is observed with FICZ (6-Formylindolo[3,2-b]carbazole), cinnabarinic acid, 5-hydroxytryptophan, N-acetyl serotonin and indol-3-yllactic acid. We propose that Trp, which docks strongly to the AhR is an AhR antagonist. Differences in AhR activation by Trp metabolites in cell systems and in vivo may be determined by the prevailing physiological conditions. The strong docking of 5-hydroxyindoles to the AhR may underpin the effects of serotonin pathway metabolites on biological processes.

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Karma Norbu

and 3 more

Introduction: Scrub typhus is a neglected life threatening acute febrile illness caused by bacteria Orientia tsutsugamushi and it is a vector-borne zoonotic disease. In 2009, scrub typhus outbreak at Gedu has awakened Bhutan on the awareness and testing of the disease.Information and data of the study highlights the need for in depth surveillance, awareness among prescribers and initiate preventive measures in the country. Methods: We used retrospective descriptive study through review of laboratory registers across three health centres in Zhemgang district, south central Bhutan. The laboratories registers have been transcribed into CSV file using Microsoft excel. Variables of interest were collected from the registers and then analysed using open statistical software R, (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.) And use of mStats package, (MyoMinnOo (2020). mStats: Epidemiological DataAnalysis. R package version 3.4.0.) Results: Of the total 922 tests prescribed for suspected scrub typhus in the three health centers in Zhemgang, only 8.2 % (n=76) were tested positive. Of these, Panbang Hospital had highest reported positive for scrub typhus with 56.6 %( n=43) followed by Yebilaptsa Hospital 35.5 %( n=27) and Zhemgang Hospital with 7.9 %( n=6). The female gender is comparably more affected as opposed to male with 57.9% (n=44) of the positive cases being female. The prevalence of scrub typhus seems to be affected by the seasonal variation as the months of Spring, Summer and Autumn together accounts for 98.7%(n=75) of total positive cases. The year 2019 noted significant scrub typhus cases accounting to 89.5 %(n=68) of the total positive cases over the two years. Conclusions:The overall tests tested positive of the scrub typhus infection within two years was 8.2%.

Selahattin Semiz

and 2 more

Monoclonal antibodies (MAbs) are powerful therapeutic tools in modern medicine and represent a rapidly expanding multi-billion USD market. While bioprocesses are generally well understood and optimized for MAbs, online quality control remains challenging. Notably, N-glycosylation is a critical quality attribute of MAbs as it affects binding to Fcγ receptors (FcγR), impacting the efficacy and safety of MAbs. Traditional N-glycosylation characterization methods are ill-suited for online monitoring of a bioreactor; in contrast, surface plasmon resonance (SPR) represents a promising avenue, as SPR biosensors can record MAb-FcγR interactions in real-time and without labelling. In this study, we produced five lots of differentially glycosylated Trastuzumab (TZM) and finely characterized their glycosylation profile by HILIC-UPLC chromatography. We then compared the interaction kinetics of these MAb lots with four FcγRs including FcγRIIA and FcγRIIB at 5 oC and 25 oC. When interacting with FcγRIIA/B at low temperature, the differentially glycosylated MAb lots exhibited distinct kinetic behaviours, contrary to room-temperature experiments. Galactosylated TZM (1) and core fucosylated TZM (2) could be discriminated and even quantified using an analytical technique based on the area under the curve (AUC) of the signal recorded during the dissociation phase of a SPR sensorgram describing the interaction with FcγRIIA (1) or FcγRII2B (2). Because of the rapidity of the proposed method (less than 5 minutes per measurement) and the small sample concentration it requires (as low as 30 nM, exact concentration not required), it could be a valuable process analytical technology for MAb glycosylation monitoring.

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