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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.

Scene flow tracks the three-dimensional (3D) motion of each point in adjacent point clouds. It provides fundamental 3D motion perception for autonomous driving and server robot. Although the Red Green Blue Depth (RGBD) camera or Light Detection and Ranging (LiDAR) capture discrete 3D points in space, the objects and motions usually are continuous in the macro world. That is, the objects keep themselves consistent as they flow from the current frame to the next frame. Based on this insight, the Generative Adversarial Networks (GAN) is utilized to self-learn 3D scene flow with no need for ground truth. The fake point cloud of the second frame is synthesized from the predicted scene flow and the point cloud of the first frame. The adversarial training of the generator and discriminator is realized through synthesizing indistinguishable fake point cloud and discriminating the real point cloud and the synthesized fake point cloud. The experiments on Karlsruhe Institute of Technology and Toyota Technological Institute (KITTI) scene flow dataset show that our method realizes promising results without ground truth. Just as human, the proposed method can identify the similar local structures of two adjacent frames even without knowing the ground truth scene flow. Then, the local correspondence can be correctly estimated, and further the scene flow is correctly estimated.   Corresponding author(s) Email: [email protected]

Leukocyte differential test is a widely performed clinical procedure for screening infectious diseases. Existing hematology analyzers require labor-intensive work and a panel of expensive reagents. Here we report an artificial-intelligence enabled reagent-free imaging hematology analyzer (AIRFIHA) modality that can accurately classify subpopulations of leukocytes with minimal sample preparation. AIRFIHA is realized through training a two-step residual neural network using label-free images of isolated leukocytes acquired from a custom-built quantitative phase microscope. By leveraging the rich information contained in quantitative phase images, we not only achieved high accuracy in differentiating B and T lymphocytes, but also classified CD4 and CD8 cells, therefore outperforming the classification accuracy of most current hematology analyzers. We validated the performance of AIRFIHA in a randomly selected test set and cross-validated it across all blood donors. Owing to its easy operation, low cost, and accurate discerning capability of complex leukocyte subpopulations, we envision AIRFIHA is clinically translatable and can also be deployed in resource-limited settings, e.g., during pandemic situations for the rapid screening of infectious diseases.  Corresponding author(s) Email:    [email protected],  [email protected]

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.

Cannabis sativa is an extraordinarily versatile species. Hemp and its cousin marijuana, both C. sativa, have been used for millennia as a source of fibre, oil and for medicinal, spiritual and recreational purposes. Because the consumption of Cannabis can have psychoactive effects, the plant has been widely banned throughout the last century. In the past decade, evidence of its medicinal properties did lead to the relaxation of legislation in many countries around the world. Consequently, the genetics and development of Cannabis as well as Cannabis-derived products are the subject of renewed attention.Here, we review the biology of C. sativa, including recent insights from taxonomy, morphology and genomics, with an emphasis on the genetics of cannabinoid synthesis. Because the female Cannabis flower is of special interest as the site of cannabinoid synthesis, we explore flower development, flowering time well as the species’ unique sex determination system in detail. Furthermore, we outline the tremendous medicinal, engineering, and environmental opportunities that Cannabis bears. Together, the picture emerges that our understanding of Cannabis biology currently progresses at an unusual speed. A future challenge will be to preserve the multi-purpose nature of Cannabis, and to harness its medicinal properties and sustainability advantages simultaneously.

Quantum chemistry must evolve if it wants to fully leverage the benefits of the internet age, where the world wide web offers a vast tapestry of tools that enable users to communicate and interact with complex data at the speed and convenience of a button press. The Open Chemistry project has developed an open source framework that offers an end-to-end solution for producing, sharing, and visualizing quantum chemical data interactively on the web using an array of modern tools and approaches. These tools build on some of the best open source community projects such as Jupyter for interactive online notebooks, coupled with 3D accelerated visualization, state-of-the-art computational chemistry codes including NWChem and Psi4 and emerging machine learning and data mining tools such as ChemML and ANI. They offer flexible formats to import and export data, along with approaches to compare computational and experimental data.

This paper responds to one by Graham Martin and colleagues, who offered a critique of my previous publications on masks for the lay public in the Covid-19 pandemic. I address their charges that my co-authors and I had misapplied the precautionary principle; drawn conclusions that were not supported by empirical research; and failed to take account of potential harms. But before that, I remind Martin et al that the evidence on mask wearing goes beyond the contested trials and observational studies they place centre stage. I set out some key findings from basic science, epidemiology, mathematical modelling, case studies and natural experiments, and use this rich and diverse body of evidence as the backdrop for my rebuttal of their narrowly-framed objections. I challenge my critics’ apparent assumption that a particular kind of systematic review should be valorised over narrative and real-world evidence, since stories are crucial to both our scientific understanding and our moral imagination. I conclude by thanking my academic adversaries for the intellectual sparring match, but exhort them to remember our professional accountability to a society in crisis. It is time to lay straw men to rest and engage, scientifically and morally, with the dreadful tragedy that is unfolding across the world.

This Supporting information includes interactive plots, videos, and data captured while performing evaluation and validation experiments for our paper. 

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.  

Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield across global regions is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control and pollination services in adjacent crops using a global dataset of 529 sites. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimize floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future.

Researchers' ability to accurately screen fossil and subfossil specimens for preservation of DNA and protein sequences remains limited. Thermal exposure and geologic age are usable proxies for sequence preservation on a broad scale but are of nominal use for specimens of similar depositional environments. Cell and tissue biomolecular histology is thus proposed as a novel proxy for determining sequence preservation potential of ancient specimens with improved accuracy. Biomolecular histology as a proxy is hypothesized to elucidate why fossils/subfossils of some depositional environments preserve sequences while others do not and to facilitate selection of ancient specimens for use in molecular studies.

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.

Introduction Frequent premature ventricular complexes (PVCs) can lead to adverse health conditions such as cardiomyopathy. The linear correlation between PVC frequency and heart rate (as positive, negative, or neutral) has been proposed as a measure to guide treatment with beta-blockers. We evaluate the robustness of this measure to day-to-day variability and measurement methodology. Methods We analyzed 82 multi-day ECG recordings collected from 48 patients with frequent PVCs (burden 1-44%). For each record, the linear correlation between PVC frequency and heart rate was computed for different 24-hour periods and using different time interval lengths to determine the PVC frequency and average heart rate. Results Using a 1-hour time interval, the correlation between PVC frequency and heart rate was consistently positive, negative or neutral on different days in 19.5% of patients. Using shorter time intervals, the correlation was consistent in 34.1-58.5% of patients. Using 1-minute time intervals emphasized a nonlinear dependence of PVC frequency on heart rate in most patients. Conclusion In patients with frequent PVCs, linear correlation of PVC frequency with heart rate is variable across different 24-hour periods and different interval lengths used to compute the average heart rate. The variable and often nonlinear dependence of PVC frequency on heart rate suggests that classification based on linear correlation should be used with caution.

Secondary forests represent significant proportions of global forest cover, with over 65% of forests in Asia classified as regenerating. While succession has been studied extensively in temperate systems, trajectories of sub-tropical forest succession remain poorly characterized in highly disturbed, urban-adjacent forests. Investigating the additive beta diversity subcomponents of Turnover and Nestedness may reveal community assembly mechanisms driving secondary succession. The present study investigated plant community assembly along a successional gradient from 7 to 70 years following the onset of succession in secondary sub-tropical forests in Hong Kong. Plant survey data for 28 plots were analysed, generating additive Simpsons and Nestedness beta diversity metrics as subcomponents of Sorenson Beta Diversity. Dissimilarity matrices were generated and modelled as a function of transformed environmental matrices of forest plant community age (years following onset of secondary succession), elevation (metres), inter-community distance (metres), soil moisture saturation (%) and soil organic carbon (g kg-1). Generalized dissimilarity models were generated for plant species Turnover and Nestedness. Nonmetric Multidimensional Scaling of plant communities was conducted with Bray-Curtis dissimilarity matrices. Our findings indicate that elevation was the primary driver of plant species Turnover, while age and inter-community distance played less prominent roles. Models of Nestedness found that plot age and soil moisture saturation were the sole drivers of Nestedness patterns in plant communities. While models of Turnover were robust, the low explanatory power of Nestedness models suggest additional unobserved factors driving patterns of plant community Nestedness during secondary succession. Turnover patterns suggest a deterministic model of community assembly, with strong patterns of species replacement between Lowland and Montaine forest types, as well as between successional age classes.

Understanding trees' growing season timing is crucial for comprehending their role in terrestrial ecosystems, including carbon dynamics. Our current determination of the growing season, based on species- and method-specific interpretations, and our understanding of the main drivers triggering the growing season yield varied results. Rethinking the growing season timing could have far-reaching implications, potentially reshaping our understanding of climate change's effect on tree growth, their carbon sequestration and future geographical distribution.

Recent theoretical advances in the One Health approach propose that greater attention should be paid to cancer pathologies due to their potential to render hosts more susceptible to infectious agents, potentially transforming them into super-spreaders within ecosystems. However, this hypothesis lacks experimental validation. Using a community of Hydra species and a commensal ciliate species (Kerona pediculus) that colonizes them, we tested whether tumoral polyps of H. oligactis, compared to healthy ones, played an amplifying role in ciliate load, potentially resulting in higher likelihood of infection for other community members through spillovers. Results revealed a higher proliferation rate of ciliates on tumoral polyps compared to healthy ones, leading to infection of other hydras, albeit with varying spillover magnitudes among recipient species. This study is the first proof of concept that tumoral individuals within communities could act as super-spreaders of symbionts within and between species, influencing biotic interactions and dynamics in ecosystems.

The total iridoid glycoside extract of Lamiophlomis rotata (IGLR) has been proven to be the main pharmacological ingredient for wound healing; however, it is still unclear, which compounds in the extract are responsible for this effect. We developed and validated a mass spectrometry imaging (MSI) method to reveal the relationship between phytochemical components and the pharmacological efficacy in IGLR. Shanzhiside methyl (SM) ester, 8-O-acetylshanzhiside methyl ester (ASM), and Phlorigidoside C (PhC) have been identified as quality markers in IGLR to accelerate wound healing by MSI method. As per MSI data with UMAP manifold analysis, these compounds overlapped in the same class with endogenous metabolites (lactate, citrate and succinate). In addition, UPLC-Q/TOF-MSn coupled with multivariate analyses for skin tissues in the normal and wound groups further confirmed the results. Furthermore, MSI data from livers and kidneys revealed that SM, ASM, and PhC absorption significantly increased, whereas their elimination rates remarkably decreased in the injured group. Collectively, the overall data demonstrated that SM, ASM, and PhC selectively increased in the new granulation tissue and that the bioavailability of these three quality markers was remarkably improved in the wound group after continuous gavage for 7 days. This protocol can be applied to reveal the relationship between phytochemical components and the pharmacological efficacy of other iridoid glycoside extracts.

Sequencing the tyrosine phosphoproteome using MS-based proteomics is challenging due to the low abundance of tyrosine phosphorylation in cells, a challenge compounded in scarce samples like primary cells or clinical samples. The broad-spectrum optimization of selective triggering (BOOST) method was recently developed to increase phosphotyrosine sequencing in low protein input samples by leveraging tandem mass tags (TMT), phosphotyrosine enrichment, and a phosphotyrosine-loaded carrier channel. Here, we demonstrate the viability of BOOST in T cell receptor (TCR)-stimulated primary murine T cells by benchmarking the accuracy and precision of the BOOST method and discerning significant alterations in the phosphoproteome associated with receptor stimulation. Using 1 milligram of protein input (about 20 million cells) and BOOST, we identify and precisely quantify more than 2,000 unique pY sites compared to about 300 unique pY sites in non-BOOST control samples. We show that although replicate variation increases when using the BOOST method, BOOST does not jeopardise quantitative precision or the ability to determine statistical significance for peptides measured in triplicate. Many pY previously uncharacterised sites on important T cell signalling proteins are quantified using BOOST, and we identify new TCR responsive pY sites observable only with BOOST. Finally, we determine that the phase-spectrum deconvolution method on Orbitrap instruments can impair pY quantitation in BOOST experiments.

Objective: The non-invasive right ventricular pressure-strain loop (PSL) represents a novel method for the quantitative assessment of right ventricular myocardial function. Given that atrial septal defect (ASD) is a prevalent congenital heart anomaly associated with right ventricular volume overload, this study aims to quantitatively assess the myocardial function of the right ventricle in ASD patients pre- and post-occlusion by noninvasive right ventricular PSL. Methods: This study included thirty-six patients diagnosed with secundum atrial septal defect (ASD group) and thirty healthy adults (control group). We compared conventional right ventricular echocardiographic parameters, right ventricular strain, and myocardial work in the ASD group before occlusion, two days post-occlusion, and three months post-occlusion, with those in the control group. Results: Prior to and two days following occlusion, the ASD group exhibited higher right ventricular global work index (RVGWI), right ventricular global wasted work (RVGWW), and right ventricular global constructive work (RVGCW) compared to the control group ( P < 0.05). Within the ASD group, post-occlusion, RVGWI, RVGCW, and RVGWW values were significantly reduced compared to pre-occlusion values ( P < 0.001). Furthermore, RVGWI and RVGCW showed a significant decrease three months after occlusion compared to two days post-occlusion ( P < 0.05). Multivariate regression analysis identified ASD diameter and pulmonary artery systolic pressure (PASP) as independent predictors of RVGWI( β = 0.405, P < 0.001; β=2.307， P=0.037) and RVGCW（β=0.350, P＜0.001; β=1.967, P=0.023). Conclusions: The non-invasive right ventricular PSL effectively demonstrates the alterations in right ventricular myocardial function in ASD patients, pre- and post-occlusion. The metrics of right ventricular myocardial work (RVMW) offer a novel indicator for evaluating right ventricular myocardial function in these patients. Moreover, ASD diameter and PASP emerge as independent determinants of RVGWI and RVGCW.

The online trend of the manosphere and feminist discourse on social networks requires a holistic measure of the level of sexism in an online community. This indicator is important for policymakers and moderators of online communities (e.g., subreddits) and computational social scientists, either to revise moderation strategies based on the degree of sexism or to match and compare the temporal sexism across different platforms and communities with real-time events and infer social scientific insights. In this paper, we build a model that can provide a comparable holistic indicator of toxicity targeted toward male and female identity and male and female individuals. Despite previous supervised NLP methods that require annotation of toxic comments at the target level (e.g. annotating comments that are specifically toxic toward women) to detect targeted toxic comments, our indicator uses supervised NLP to detect the presence of toxicity and unsupervised word embedding association test to detect the target automatically. We apply our model to gender discourse communities (e.g., r/TheRedPill, r/MGTOW, r/FemaleDatingStrategy) to detect the level of toxicity toward genders (i.e., sexism). Our results show that our framework accurately and consistently (93% correlation) measures the level of sexism in a community. We finally discuss how our framework can be generalized in the future to measure qualities other than toxicity (e.g. sentiment, humor) toward general-purpose targets and turn into an indicator of different sorts of polarizations.

Peptides play an indispensable role in various biological functions and show therapeutic potential. The forest musk deer, an important source of musk, is a focal species in traditional medicine. While cell culture techniques offer a sustainable alternative for musk production, the complexity of peptide components produced by these methods remains poorly understood. To bridge this knowledge gap, we compared the peptidomic profiles of secretions from cultured musk gland cells with those of natural musk cells using the EASY-nLC 1000 UHPLC (Ultra-High Performance Liquid Chromatography) system. Our analysis revealed similarities and notable differences between the peptide profiles of cultured cell secretions and those of natural musk, with significant implications for the biosynthesis and chemical composition of musk. This study provides critical insights into the peptidomic differences between cultured cell secretions and natural musk, highlighting the challenges and potential of using cell culture techniques for the sustainable production of musk components. Future research should focus on refining conditions to more closely emulate the natural biosynthetic pathways of musk peptides.

Title: Assessment of sIgE to rLep d 2 for DetectingLepidoglyphus destructor SensitizationConclusion: The novel recombinant allergen rLep d 2 exhibits excellent specificity, although its sensitivity is lower compared to specific IgE tests and skin prick tests using Lepidoglyphus destructor . Its additional diagnostic utility for respiratory allergies related to L. destructor is minimal.To the Editor:Recently, rLep d 2 has been introduced to diagnose IgE-mediated allergy to Lepidoglyphus destructor. We aimed to analyze the sensitivity, specificity, and likelihood ratios of sIgE against rLep d 2.We retrospectively analyzed 95 sera of patients previously diagnosed with respiratory allergy to L destructor , to whom an IgE determination of L destructor had been requested. The protocol was approved by the Hospital Ethics Committee for Clinical Research (PI 2023/09/1425). Material and methods are specified in Supplementary material.Statistically significant differences were found between patients sensitized and not sensitized to L destructor . Patients with a sIgE positive to L destructor were younger, had a higher percentage of asthma and moderate/severe persistent rhinitis, and had higher levels of total IgE and sIgE to rLep d 2 and rDer p 2 than non-sensitized patients. (Table 1).There was a high correlation between L destructor and rLep d 2 (R=0.940, p<0.001), although no correlation was observed between L. destructor and r Der p 2 (R= 0.117, p= 0.260) (Figure S1).The sensitivity of sIgE to rLep d 2 was 71.64% (95% CI, 59.31-81.99), and specificity was 96.43% (95% CI, 81.65-99.91). PLR was 20.06 (95%CI, 2.91-138.28) and NLR 0.29 (95% CI, 0.20-0.43). The Receiver Operating Characteristic (ROC) curve for sIgE to rLep d 2 had an area under the curve of 0.931 (Figure S2). The results of the patients’ test are summarized in Figure 1.This is the first study to examine the accuracy of the commercially available major allergen rLep d 2 in a population of patients allergic and non-allergic to L destructor with rhinitis and/or asthma. Good sensitivity (71.64%), excellent specificity (96.43%), remarkable PLR (20.06) and NRL (0.29), and a noteworthy ROC result (0.931) were observed.Data analysis showed a high correlation between sIgE to rLep d 2 and sIgE to L destructor (0.94) (Figure S1A), much higher than that previously obtained by Johansson et al. (1), who used a non-commercial recombinant extract of Lep d 2, finding a correlation coefficient of 0.70. Additionally, the lack of correlation between sIgE to rDer p 2 and sIgE to L destructor , with a correlation coefficient of 0.117 (Figure S1B), agrees with the lack of cross-reactivity between group 2 allergens of L destructor andD pteronyssinus (2). Therefore, most patients who test positive for rLep d 2 and rDer p 2 can be considered co-sensitized.The sensitivity and specificity data for sIgE to rLep d 2 indicate that a positive result suggests sensitization to L. destructor . In contrast, a negative result does not necessarily rule out sensitization, as almost 30% of patients can still be sensitized to L destructor . The PLR of 20.06 provides robust evidence for L destructor allergy when rLep d 2 values are ≥0.35 kU/L. However, it is noteworthy that the ability to exclude L destructor allergy is weaker when rLep d 2 values fall below that threshold.Patients’ test results (Figure 1) suggest that both SPT and sIgE should be used when evaluating a patient with suspected allergy to L destructor . In addition, 19 patients had sIgE positive to L destructor but negative sIgE to rLep d 2. It could happen that some patients may have been sensitized to allergens other than Lep d 2. Accordingly, rLep d 2 should not be initially used when evaluating a patient with a suspected allergy to L destructor . Notwithstanding, sIgE against Lep d 2 might be helpful before initiating specific immunotherapy with L destructor (3).To conclude, despite an excellent specificity, determining sIgE to rLep d 2 does not seem to offer additional diagnostic value when compared SPTs and/or sIgE to L destructor .REFERENCESJohansson E, Eriksson TLJ, Olsson S, et al. Evaluation of Specific IgE to the Recombinant Group 2 Mite Allergens Lep d 2 and Tyr p 2 in the Pharmacia CAP System. Int Arch Allergy Immunol. 1999;120(1):43-49.Parvaneh S, Johansson E, Elfman LH, et al. An ELISA for recombinant Lepidoglyphus destructor, Lep d 2, and the monitoring of exposure to dust mite allergens in farming households. Clin Exp Allergy. 2002 Jan;32(1):80-6Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J. 2020 Feb 25;13(2):100080.

Habitat fragmentation is a major driver of genetic differentiation and genetic diversity loss in endangered species due to restricted gene flow, genetic drift, and inbreeding. However, the impact on ectomycorrhizal (ECM) fungi remains unexplored, despite their critical roles in forest ecosystems. In this study, we investigated the population genetic structure of the ECM fungus Rhizopogon togasawarius, which specifically colonizes Pseudotsuga japonica across its entire distribution range. Both symbionts are found only in small, fragmented forests in Japan; they are designated as endangered species on the IUCN Red List. We assessed the population genetic structure of 236 R. togasawarius specimens collected from five remaining populations, distributed in two regions separated by a sea channel. Microsatellite analyses using 20 loci revealed strong genetic differentiation among populations (FST = 0.255), even in the nearest population pair separated by a distance of only 8 km (FST = 0.075), indicating extremely limited gene flow between populations. Population history analyses implied that population divergence occurred approximately 2200 generations ago between the two regions, and nearly 1000 generations ago between the nearest populations within the Shikoku region. Because of prolonged genetic isolation, significant inbreeding was confirmed in four of five populations, where effective population sizes became very small (Ne = 9.0–58.0). Although evaluation of extinction risks for microorganisms is challenging, our conservation genetic results indicated that habitat fragmentation increases extinction risk through population genetic mechanisms, as demonstrated in plants and animals, and therefore should not be overlooked in biodiversity conservation efforts.

Alcohol consumption and high-fat diets often coincide in Western society, exerting negative synergistic effects on the liver. While many studies have demonstrated the impact of ALD and NAFLD on organ protein expression, none have offered a comprehensive view of the dysregulation at the level of the membrane proteome. In this study, we utilize peptidisc and solvent precipitation (SP4) methods to isolate and compare the membrane protein content of the liver with its unique biological functions. Using mice treated with a high-fat diet and ethanol in drinking water, we identified 1,563 liver proteins, with 46% predicted to have a transmembrane segment. Among these, 106 integral membrane proteins are dysregulated compared to the untreated sample. Gene ontology analysis reveals several dysregulated membrane processes associated with lipid metabolism, cell adhesion, xenobiotic processing, and mitochondrial membrane formation. Pathways related to cholesterol and bile acid transport are also mutually affected, suggesting an adaptive mechanism to counter the steatosis of the liver model. Our peptidisc-based membrane proteome profiling thus emerges as an effective way to gain insights into the role of the transmembrane proteome in disease development, warranting further in-depth analysis of the individual effect of the identified dysregulated membrane proteins.