ABSTRACT OBJECTIVE: To detect serum placental growth factor levels and uterine artery doppler pulsatility index for predicting pre-eclampsia and assess their association with the severity of pre-eclampsia. DESIGN: Prospective observational study SETTING: Tertiary care centre POPULATION: All antenatal women from 11 to 13+6weeks gestation attending antenatal clinic during study period. METHODS: This involved 160 antenatal women, from 11-13+6 weeks gestation. Serum PlGF levels and UA doppler mean P.I measured and patients were followed up upto delivery and observed for the development of pre-eclampsia and its severity. MAIN OUTCOME MEASURES: PIGF Value cut-off was 40.33pg/ml with the sensitivity of 97.5 % and Specificity was 98.3%. For the PI Value of 1.85 the sensitivity was found to be 74.4% and Specificity was found to be 92.5%. RESULTS: Mean serum PlGF levels for pre-eclampsia patients was 25.09pg/ml and for normotensive patients mean PlGF level was 65.05pg/ml. Mean UA doppler P.I for pre-eclampsia patients was 2.02 and for normotensive patients was 1.39. Mean PI value increased with increasing severity of preeclampsia. CONCLUSION: Early recognition of women will help initiation of prophylactic measures and enhanced surveillance. First trimester UA Doppler with serum PlGF together with maternal characteristics can be used as a reliable screening test for preeclampsia prediction and to reduce feto-maternal morbidity KEYWORDS: uterine artery (UA) doppler pulsality index (P.I), placental growth factor levels(PlGF), pre-eclampsia, eclampsia

This research explores the effects of thermal and solute buoyancy forces on the unsteady boundary-layer (BL) stream through an upright porous flat plate with heat generation. The investigated fluid is viscid, impermeable, and electrically conductive. Thermo and solute buoyancy forces cause the mechanisms of thermal and material transfer. The nonlinear time-dependent partial differential equations (PDEs) about continuity, momentum, energy, and concentration are examined through suitable modifications. After mathematical modeling, an explicit finite difference method (EFDM) is used to solve a group of nonlinear dimensionless PDEs and appropriate boundary conditions. The detailing of the EFDM procedure due to the considered model is well-stated step by step. The validity of EFDM coding is conducted by reproducing similar previously available results. The mathematical formulation, stability, and convergence explored are also recognized. Searching for an appropriate uniform meshing and steady state condition is performed carefully. The existence of the pertinent parameters in this finite difference modeling is also checked. The thermo-physical consequences of inflowing physical values (buoyancy force and heat generation) on the velocity, temperature, and concentration distribution are scrutinized. The deviations in local and average skin friction coefficients, heat, and material transfer rates are also examined for physical curiosity in engineering research. The above-illustrated model equations are numerically simulated using LAHEY FORTRAN 95 v6.2. For graphical representation, Tecplot 365, and for data analysis, Microsoft Excel 2023 are used. The significant finding of this research reveals that the fluid velocity upsurges as the buoyancy intensifies, and the rising temperature generation enhances the thermal-material transport rates. The observed behavior is attributed to the thermal buoyancy force, which produces a pressure gradient. To compare the current modeling result, we correlate these findings to those of other research available in the literature.

Objective: This qualitative study investigated perspectives on causes of eating disorders as experienced by those caring for affected individuals with an eating disorder in New Zealand. Method: Participants were nine carers of affected individuals, recruited from an online survey, who consented to semi-structured qualitative interviews. Inductive thematic analysis was undertaken to identify themes from the data. Results: The overall theme informed by the data was ‘It’s complicated’, reflecting carer perspectives that eating disorder causes were complex and multifactorial. This theme was supported by sub-themes of; ‘it’s like Swiss cheese’; ‘it came out of the blue’ and ‘in hindsight maybe…’. Most participants indicated potential eating disorder causes had not been formally explored with treatment teams, although carers had reflected on possible causality across the treatment journey. Conclusion: All participants expressed uncertainty when reflecting on what factor(s) may have caused an eating disorder in their family member. Participants reflected that causes were likely a complex combination of environmental, social, psychological and biological influences. Future research would benefit from data analysis of dyads of carers and affected individuals who identify significant recovery from the eating disorder, in order to reflect back upon possible causes without the demands of treatment or continuing eating disorder symptomatology.

Phostensin (PTS) encoded by KIAA1949 is a scaffold protein. It can bind to protein phosphatase 1 (PP1), F-actin, Eps 15 homology domain-containing protein 1 (EHD1) and EHD4. PTS contains both PP1-binding and actin-binding motifs. Most EHD-binding proteins contain a consensus motif, Asn-Pro-Phe (NPF) motif, which interacts with the C-terminal EH domain of EHD proteins. Nevertheless, the NPF motif is absent in PTS. The binding motif for PTS to associate with EHD1 (or EHD4) remains unknown. Here, we used structure-function, far western blotting and GST pull-down assays to investigate this issue and identified that PTS-α binds to EHD1 (or EHD4) through the region of residues 60-80 which contains a consensus motif, 64ILV(X) 4(L/V)RL 74S. This novel motif was also found in the vacuolar protein sorting 35 (vps35) of retromer, an EHD1-associating complex and regulating retrograde trafficking, Replacement of 64ILV(X) 4(L/V)RL 74S with 64AAA(X) 4(L/V)RL 74S or with 64ILV(X) 4AEA 74A significantly reduces the binding efficiency of PTS-α to either EHD1 or EHD4. Overexpression of the PTS-β in 293T cells attenuated the endocytic trafficking of transferrin. However, this attenuation of transferrin in endocytic trafficking was disrupted when 293T cells overexpressed the mutant PTS-β with a defective EHD-binding motif, suggesting that PTS-β can regulate the endocytic recycling via associating with EHD1 or EHD4.

Organisms from all kingdoms of life release membrane vesicles, which are tiny and spherical structures made of a lipid bilayer. Membrane vesicles carry out a number of functions, such as forming new cell membranes, removing waste products from the cell, and transporting lipids and other substances from parent to recipient cells. The payloads often contained in the vesicles are sorted via the endosomal sorting complex required for transport (ESCRT) pathway in a stepwise manner. Alterations to this endomembrane system reduces formation of vesicles and aberrant endosomal compartments. Furthermore, in pathogenic fungi, the deletion of ESCRT genes negatively effects virulence and growth, suggesting the ESCRT pathway has links to disease. However, only a few fungal species have to date been evaluated for the ESCRT pathway. In this review, we evaluate recent developments in the ESCRT pathway of fungi that infect plant hosts and its role in pathogenesis. This will provide an overview of EV-mediated cell-cell communication during host-pathogen interactions.

A document by Kyle Coblentz. Click on the document to view its contents.

The relationship between biodiversity and ecosystem function (BEF) captivates ecologists, but the factors responsible for the direction of this relationship remain unclear. While higher ecosystem functioning at higher biodiversity levels (‘positive BEF’) is not universal in nature, negative BEF relationships seem puzzlingly rare. Here, we develop a dynamical consumer-resource model inspired by microbial decomposer communities in pitcher plant leaves to investigate BEF. We manipulate microbial diversity via controlled colonization and measure their function as total ammonia production. We test how niche partitioning among bacteria and other ecological processes influence BEF in the leaves. We find that a negative BEF can emerge from reciprocal interspecific inhibition in ammonia production causing a negative complementarity effect, or from competitive hierarchies causing a negative selection effect. Absent these factors, a positive BEF was the typical outcome. Our findings provide a potential explanation for the rarity of negative BEF in empirical data.

In the Arctic tundra, recurrent periods of food scarcity force predators to rely on a wide variety of resources. In particular most predators use ungulate carcasses as an alternative food supply, especially in winters when live preys are scarce. As important and localized resource patches, carrion promotes co-occurrence of different individuals, and its use by predators is likely to be affected by interspecific competition. Here, we studied how interspecific competition and resource availability impact winter use of carrion by Arctic and red foxes in low Arctic Fennoscandia. We predicted that presence of red foxes limits Arctic foxes' use of carrion, and that the outcome of competition for carrion depends on the availability of alternative food resources, such as rodents. We monitored Arctic and red fox presence at experimentally supplied carrion using camera traps, between 2006 and 2021 in late winter. Using a multi-species dynamic occupancy model at a week-to-week scale, we evaluated use of carrion by foxes, while accounting for the presence of competitors, rodent availability and supplemental feeding provided to Arctic foxes. Competition primarily affected carrion use by increasing both species' probability to leave occupied carcasses to a similar extent, suggesting a symmetrical avoidance. Rodent abundance was associated with an increase in the probability of colonizing carrion for both species. For Arctic foxes, however, this increase was only observed in carcasses unoccupied by red foxes, showing greater avoidance when alternative preys are available. Contrary to expectations, we did not find strong signs of asymmetric competition for carrion in winter. Our results suggest that interactions for resources at a short time scale are not necessarily aligned with interactions at the scale of the population. In addition, we found that competition for carcasses depends on the availability of other resources, suggesting that interactions between predators depend on the ecological context.

Aim: Cancer treatment long-term complications for men include testicular dysfunction and possible infertility. Nonetheless, the evidence for this risk for various chemotherapies is insufficient. This is the case with bleomycin, which, aside from its well-studied lung toxicity, has received little research attention for its effect on male reproduction. This systematic review sought evidence for the effects of bleomycin-cancer treatment on testicular function and fertility. Methods: PubMed and Web of Science were searched using specific search terms, and seven animal studies met all inclusion criteria and provided an analysis of bleomycin gonadotoxicity. Results: Overall, the results suggest that bleomycin is gonadotoxic. It has the same effect on the nuclear DNA integrity of rodent sperm as it does on cancer cells. Bleomycin-induced changes in rodent testis histopathology are most noticeable at seminiferous tubule structure level. Bleomycin also significantly decreases rodents´ seminal conventional parameters and testosterone levels, the latter of which is consistent with increased induced degeneration of Leydig cells. Seminiferous tubule necrosis and alterations in tunica albuginea thickness in rodent testis are signs of a bleomycin-induced inflammatory process similar to the pulmonary one. Conclusion: More research, particularly human research, is required to provide strong evidence on how bleomycin affects human testicular function, including hormone function; and whether is gonadotoxic, whether it has a transient or permanent effect; how it may affect offspring; and how it can be reduced. Despite this, the current findings have important implications for clinicians in counseling patients about fertility risk and guiding requirements for fertility preservation strategies.

Background and Purpose: Various plant-derived compounds can activate immune responses against bacterial infections, and this property contributes to them being developed as effective and safe adjuvants for vaccines. In this study, the potential adjuvant effects of a galactolipid-enriched fraction generated from the medicinal plant Crassocephalum rabens (designated CRA) were evaluated. Experimental Approaches: Heat shock protein 60 of periodontal disease pathogen Actinobacillus actinomycetemcomitans (AaHSP60) was taken as an antigen and mixed with CRA. The AaHSP60/CRA mixture was then injected subcutaneously into the BALB/c mice. Titers and affinity of specific antibodies were measured by ELISA. Cytokine profiles in mouse serum or culture media of AaHSP60/CRA-treated splenocytes were analyzed by cytokine multiplex assay and ELISA kits. B cell differentiation and macrophage activation were determined by phenotyping. Key Results: CRA dramatically enhanced specific antibody titers and induced Ig class switch as shown by increases in the IgG2a, IgG2b and IgG3 proportions of total Ig in mouse serum. Furthermore, CRA-induced anti-AaHSP60 antibodies had cross-reactivity to other bacterial HSP60s. Cell based and animal results showed that CRA triggered IL-21 and B cell activating factor (BAFF) release that led to B cell differentiation. CRA also enhanced cell proliferation, uptake ability, and antigen presentation in mouse phagocytes. Conclusion and Implications: CRA served as a vaccine adjuvant that enhance mouse immunity against pathogenic antigens. CRA strengthened the activation and capabilities of phagocytes and B cells. Therefore, CRA may be a promising adjuvant for bacterial vaccines including periodontal disease.

Background and Purpose: The classical theory of receptor action has been used for decades as a powerful tool to estimate molecular determinants of ligand-induced receptor activation (i.e. affinity and efficacy) from experimentally observable biological responses. However, it is also a well-recognized fact that the receptor-binding and activation mechanisms, and the parameters thereof, described in the classical theory contradict with the modern view of receptor activation based on allosteric principles. Experimental Approach: We used mathematical analysis, along with some numerical simulations, to answer the key question as to what extent the classical theory is compatible -if at all- with the modern understanding of receptor activation. Key Results: Here, we showed conclusively that 1) receptor activation equations based on allosteric principles contain the logic of the classical theory in disguise, and therefore, 2) estimates of “intrinsic efficacy” () obtained by means of classical techniques (i.e. null methods or fitting the operational model to concentration-response data) are equivalent to the allosteric coupling factors that represent the molecular efficacy of ligands. Conclusion and Implications: Thus, we conclude that despite the right criticisms it has received so far, the classical theory may continue to be useful in estimating ligand efficacy from experimental data, if used properly. Here, we also provide rigorous criteria for the proper use of the theory. These findings not only have implications on ligand classification, but also resolve some long lasting discussions in the field of bias agonism in GPCR, which requires reasonable estimates of relative ligand efficacies at different signalling pathways.

Textures in Molybdenum-Rhenium alloys are inevitable during thermal fabrication. [110] and [100] are common orientations in Molybdenum-Rhenium alloys and effect mechanical responses. However, orientation dependence of mechanical responses in Molybdenum-Rhenium alloys is not quite clear yet. To clarity this problem, micro-pillar compression tests are conducted in grains with orientation [100] and [110] separately. Orientation-dependent compressive properties are found in Mo-14Re and Mo-42Re, but are not found in Mo and Mo-5Re, which may be attributed to activated muiti-slip planes as increased Re. Solid solution effect of Re not only rely on orientations, but also on Re content. Softening effect occurs in both [100] and [110] Mo-5Re. while, strong strengthening effect happens in [110] Mo-14Re and Mo-42Re. Our research clarifies that Mo-Re alloys with [110] orientation / texture could be preferred to obtain good strengthening effect.

Infective endocarditis caused by K. oxytoca: A Case Report

Resilience assessment is a widely-used tool to evaluate the ability of an object (e.g., an individual structure, or a system consisting of multiple interacting structures) to withstand, recover from, and adapt to disruptive events. This paper proposes a novel concept of “nonresilience curve”, which measures the nonresilience (complement of resilience) of an object of interest conditional on a specific hazard intensity. It is by nature an extension of the well-established fragility curves, integrating the multiple damage states of a post-hazard object. The applicability of the proposed nonresilience curve to individual structures and systems (including series systems, parallel systems, and more general & complicated systems) has been demonstrated in this paper. It is also preliminarily shown that the shape of the cumulative distribution function of a lognormal distribution is suitable to approximate the nonresilience curve, if only limited data points associated with the target nonresilience curve are available. Since the nonresilience curve is a function of the hazard intensity measure, one can estimate the nonresilience of an object in a fully probabilistic manner by additionally taking into account the uncertainty associated with the intensity measure. The proposed nonresilience curve can be further extended to formulate nonresilience surface, which is a joint function of both the intensity measure and the available resource that supports the post-hazard recovery process. The nonresilience curve is promising to be adopted in engineering practice for resilience assessment and resilience-based design of civil structures and infrastructures.

Monolobated Megakaryocytes in Diamond Blackfan Anemia withRPL5 Mutation at Disease Presentation Mimicking Myelodysplastic Syndrome

Polyploidy occurs across the tree of life and is especially common in plants. Because newly formed cytotypes are often incompatible with their progenitors, polyploidy is also said to trigger “instantaneous” speciation. If a polyploid can self-fertilize or reproduce asexually, it is even possible for one individual to produce an entirely new lineage. How often this extreme scenario occurs is unclear, with most studies of wild polyploids reporting multiple origins. Here, we explore the evolutionary history of the wild allotetraploid Mimulus sookensis, which was formed through hybridization between self-compatible, diploid species in the Mimulus guttatus complex. We generate a chromosome-scale reference assembly for M. sookensis and define its distinct subgenomes. Despite previous reports suggesting multiple origins of this highly selfing polyploid, we discover patterns of population genomic variation that provide unambiguous support for a single origin, which we estimate occurred ~71,000 years ago. One M. sookensis subgenome is clearly derived from the selfer M. nasutus, which, based on organellar variation, also appears to be the maternal progenitor. The ancestor of the other subgenome is less certain, but it shares variation with both M. decorus and M. guttatus, two outcrossing diploids that overlap broadly with M. sookensis. Whatever its precise ancestry, this study establishes M. sookensis as an example of instantaneous speciation, likely facilitated by the polyploid’s predisposition to self-fertilize. With a reference genome for M. sookensis now available and its origin clarified, this wild tetraploid is poised to become a model for understanding the genetic and evolutionary mechanisms of polyploid persistence.

The identification of blister, bite, and ghost cells on a blood smear as valuable clues for diagnosing G6PD deficiency in a 3-year-old child Author List: Zulin Xie1, Wei Li1, Xueyan Chen21. Department of Laboratory Medicine, Liuzhou People’s Hospital, Liuzhou, Guangxi2. Clinical Laboratory, Department of Clinical Laboratory, People’s Hospital of Longhua Shenzhen, Shenzhen, China, 518109.Corresponding author: Xueyan Chen Clinical Laboratory, Department of ClinicalLaboratory, The People’s Hospital of Longhua Shenzhen, Shenzhen, China. 518109,China. Fax: +86 755 27741585. E-mail address:13632546963 @163.comTo the Editor:Glucose-6-phosphate dehydrogenase(G-6PD) deficiency is the most prevailing enzyme defect in humans, affecting over 400 million individuals worldwide [1]. The most prevalent life-threatening symptoms associated with G-6PD deficiency are acute hemolytic crises upon exposure to triggering factors like medications, infections, or consumption of fava beans. Managing acute hemolytic crises in patients without medical history of G-6PD deficiency often presents a significant challenge for hematologists and emergency department (ED) physicians. The identification of morphological abnormalities remains crucial for the differential diagnosis of hemolytic anemia [2]. In certain cases, such abnormalities can only be determined through the examination of a blood smear.A 3-year-old boy was brought to the emergency department with generalized jaundice and hematuria after taking oral antipyretic ibuprofen one day ago. The physical examination revealed pale lips, indicating a glaring presence of severe anemia. Blood tests demonstrated severe microcytic anemia (icteric plasma, hemoglobin 43g/L, hematocrit 14.4%, mean corpuscular volume 75fl). The urine appeared to be a deep shade of red, showing the presence of occult blood (3+), and bilirubin (2+). Peripheral blood smear revealed the presence of considerable anisopoikilocytosis, blister cells (“hemi-ghost” cells) characterized by irregularly contracted hemoglobin from one side and half-empty cytoplasm), and occasional bite cells (Figure 1 ). Furthermore, ghost cells were observed, which are erythrocyte membranes devoid of hemoglobin (Figure 1 ). Further studies confirmed hemolysis with a high reticulocyte count (0.268×1012/L), increased unconjugated bilirubin (79μmol/L), increased lactate dehydrogenase (1475U/L), decreased haptoglobin (< 0.1 g/L). We strongly advised the emergency physician to consider the possibility that the patient was experiencing an acute hemolytic crisis stemming from G6PD deficiency. The patient was promptly admitted to the pediatric ward for a thorough examination. The direct and indirect antiglobulin tests yielded negative results, effectively ruling out the presence of immune-mediated acute hemolysis. However, the G6PD enzyme activity assay yielded normal results. A follow-up G6PD assay conducted six weeks after the patient’s discharge revealed a significantly reduced enzyme activity (148 u/L, reference range >1300 u/L), solidifying the clinical suspicion of G6PD deficiency in the patient. Meanwhile, a missense variant in exon 12: c.1466G>T (p. Arg 489Leu) (hemizygous) was detected in the G6PD gene as a pathogenic mutation reported in the literature [HGMD cm910163] (Figure 2 ).In our study, we noted a significant drop in hemoglobin levels within the initial 24 hours following the initiation of ibuprofen therapy in a child suffering from fever, accompanied by the emergence of hemoglobinuria and irregular red blood cell (RBC) morphology in the blood smear. Blood smears play a critical role in diagnosing this disorder due to two significant reasons. Firstly, it is considerably faster when compared to the results determined solely by the measured activity of G6PD. When taken into account alongside the patient’s ethnic origin and medical history, a preliminary diagnosis can be established. Secondly, in the case of a hemolytic crisis, it is important to note that even if the G6PD assay yields normal results, a diagnosis of G6PD deficiency can still be suggested through blood smears, as exemplified in the current case. The reason why C6PD deficiency exhibits normal assay results after an acute hemolytic crisis is that the abnormal cells tend to undergo lysis more readily, leading to a predominance of cells with the normal allele in the bloodstream [2]. Hence, the identification of typical RBC morphological features in the blood smear suggests the need for multiple measurements of G6PD activity following the resolution of the acute hemolytic episode. Hemoglobinuria serves as a significant indicator of intravascular hemolysis and is a characteristic of drug-induced acute hemolysis in individuals with G6PD deficiency [3]. In contrast, drug-induced acute hemolysis typically manifests as extravascular hemolysis without hemoglobinuria in patients with normal red blood cells.In conclusion, the diagnostic process was significantly aided by blood smear analysis, highlighting its crucial role in this particular scenario.

Adaptive radiation as a result of ecological opportunity can have profound effects on the evolutionary outcome of species. On coral reefs, parrotfishes have been considered as one of the most dramatic examples of adaptive radiation unique in their extreme dietary specialisation. Using abrasion-resistant biomineralized teeth, parrotfishes are able to mechanically extract protein-rich micro-photoautotrophs growing in and amongst reef carbonate material. This unique ability to exploit a previously untapped trophic resource is thought to have led to the early diversification of the parrotfishes. In order to better understand the key evolutionary innovations leading to the success of these dietary specialists, we sequenced and analysed the genome of the spotted parrotfish (Cetoscarus ocellatus). Our findings reveal significant expansion, selection, and duplication within several gene families responsible for detoxification, including the cytochrome p450 gene family and non-cyp450 carboxylesterases. We find preliminary evidence that the structural mechanism responsible for the extreme hardness and biomineralization of parrotfish teeth may be a result of poly-glutamine expansion in the enamel protein ameloblastin. We also detect expansion and selection for several genes related to pigmentation and sequential hermaphroditism. Together, these results highlight a potentially complex interplay of adaptive radiation and sexual selection operating on coral reef ecosystems.

Species interactions and abiotic factors are important determinants of abundance and distribution, but accounting for biotic interactions is complicated by the fact that interactions occur at the individual-level at unknown spatial scales. Ignoring individual-level interactions can yield incorrect conclusions about biotic interactions when analyzing aggregated count data or presence-absence data. We present a hierarchical species distribution model that includes a Markov point process in which an individual’s location is dependent upon both abiotic variables and the locations of individuals of another species. The model can be regarded as a thinned point process in which encounter probability is a function of the distance between individual activity centers and survey locations. We applied the model to spatial capture-recapture data on two ecologically similar songbird species – hooded warbler (Setophaga citrina) and black-throated blue warbler (Setophaga caerulescens) – that segregate over a climate gradient in the southern Appalachian Mountains, USA. In spite of coarse spatial segregation and many ecological similarities between the two species, we found minimal evidence of spatial competition. There were strong, and opposing effects of climate on spatial variation in population densities, but spatial competition did not influence their distributions. A small simulation study indicated that the model can identify the distinct effects of environmental variation and biotic interactions on co-occurring species distributions. Unlike previous statistical models that attempt to infer competition from species-level co-occurrence data, the framework proposed here can be used to investigate how population-level patterns emerge from individual-level processes, while also allowing for inference on the spatial scale of biotic interactions. Our finding of minimal spatial competition between black-throated blue warbler and hooded warbler adds to the growing body of literature suggesting that, contrary to early theory from biogeography, abiotic factors may be more important than competition at low-latitude range margins.

Plastering is dominated manually, exhibiting low levels of automation and inconsistent finished quality. A comprehensive review of literature indicates that extant plastering robots demonstrate a subpar performance when tasked with rectifying defects in transition area. The limitations encompass a lack of capacity to independently evaluate the quality of work or perform remedial plastering procedures. To address this issue, this research describes the system design of the Puttybot and a paradigm of plastering to solve the stated problems. The Puttybot consists of a mobile chassis, lift platform, and a macro/micro manipulator. The force-controlled scraper parameters have been calibrated to dynamically modify their rigidity in response to the applied putty. This strategy utilizes Convolutional Neural Networks to identify plastering defects and executes the plastering operation with force feedback. This paradigm’s effectiveness was validated during an autonomous plastering trial wherein a large-scale wall was processed without human involvement.

Background and Purpose: Randomized Control Trials (RCTs) are the gold standard for establishing causality in drug efficacy, However, they have limitations due to strict inclusion criteria and complexity. When RCTs are not feasible, researchers turn to observational studies. Explainable AI (XAI) models provide an alternative approach to understanding cause-and-effect relationships. Experimental Approach: : In this study, we utilized an XAI model with a historical COVID-19 dataset to establish the hypothesis of drug efficacy. The datasets consisted of 3,307 COVID-19 patients from a hospital in Delhi, India. Eight XAI models were employed to assess factors influencing COVID-19 mortality. LIME and SHAP interpretability techniques were applied to the best-performing ML model to determine feature importance in outcome. Key Results: The XGBoost ML classifier outperformed (weighted F1 score, MCC, accuracy, ROC-AUC, sensitivity and specificity score of 91.7%, 58.8%, 91.3%, 92.2% 93.8%, and 70.2%, respectively) other models and the SHAP summary plot enabled the identification of significant features that contributes to COVID-19 mortality. These features encompassed comorbidities like renal and cardiac diseases and tuberculosis. Additionally, the XAI models revealed that medications such as enoxaparin, remdesivir, and ivermectin did not exhibit preventive effects on mortality Conclusion and Implications: While XAI models offer valuable insights, they should not replace RCTs as a priority for ensuring the safety and effectiveness of new drugs and treatments. However, XAI models can serve as valuable tools for suggesting future research directions and aiding clinical decision-making, particularly when the efficacy of a drug in a controlled trial is uncertain.

Background and Purpose: Abnormal activation of the NLRP3 inflammasome in macrophages is closely associated with Ulcerative colitis (UC), and targeting the NLRP3 inflammasome has been proposed as a potential therapeutic approach, but the underlying mechanism by which it regulates intestinal inflammation remains unclear. Anemoside B4 (AB4) has anti-inflammatory activity, but whether it alleviates UC by inhibiting the activation of NLRP3 inflammasome remains unclear. More importantly, the molecular targets of AB4 remain unknown. Experimental Approach: We explored the role of AB4 in the development of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) mice and its effect on NLRP3 inflammasome. We isolated intestinal macrophages and epithelial cells, and validated them in DSS-induced NLRP3-deficient (NLRP3-/-) mice. The target and molecular mechanism of AB4 were identified in LPS-induced macrophages in vitro and DSS-induced macrophage-specific CD1d depletion (CD1d-/-) mice in vivo. Key Results: This study showed that AB4 had a strong anti-inflammatory effect DSS-induced colitis in WT mice, whereas the protective effects were lost in NLRP3-/- mice. AB4 inhibited the activation of NLRP3 inflammasome in colonic macrophages without affecting intestinal epithelial cells. Mechanistically, AB4 might target CD1d thus reducing the AKT-STAT1-PRDX1-NF-κB signaling pathway, eventually inhibiting the activation of NLRP3 inflammasome. Macrophage-specific CD1d depletion had been shown to reverse the protective effect of AB4. Conclusions and Implications: Our data showed that AB4 attenuated DSS-induced colitis by inhibiting CD1d-dependent NLRP3 inflammasome activation in macrophages. Therefore, as a natural product with high safety index, AB4 might be considered a promising candidate drug for the treatment of colitis.

Exercise induced eosinophil responses: normal cell counts with a marked decrease in responsivenessTo the Editor,Type II inflammation is characterized by elevated blood eosinophils which makes these cells an important diagnostic and treatment target in, for instance, severe asthma. Therefore, blood eosinophil numbers are a main inclusion criterion for many clinical studies that investigated the treatment of eosinophilic asthma with anti-IL5(Rα). However, there is no consensus on cut-off values for blood eosinophils during inclusion, as evidenced by a high variability between studies, ranging from 150 to 400 cells/µL. Moreover, the range of blood eosinophils in a healthy population, without confounding factors for increased blood eosinophils, is 30 – 330 cells/µL in males and 30 – 310 cells/µL in females. This implies that the cut-off values used for clinical studies greatly overlap with blood eosinophil counts that are found in the healthy population. This inherently poses a problem as eosinophil blood counts seem to be inadequate to use for diagnosing eosinophilic disease.This overlap in eosinophil counts between patients and the healthy population limits the application of eosinophil numbers for discriminating between health and several inflammatory diseases. A more promising approach in diagnosing eosinophilic disease is to combine eosinophil numbers with their activation status. Unfortunately, there is surprisingly little evidence that blood eosinophil counts correlate with their activation status and/or responsiveness in vivo in disease. This lack of correlation can be caused by ex vivo activation and/or their homing to the lung leaving behind non-activated cells in the blood.To circumvent ex vivo activation, we analyzed blood eosinophils activation status directly after venipuncture with a fast, automated, point-of-care, mobile flow cytometer (AQUIOS CL, Beckman Coulter). As exercise can be used as a model to modulate eosinophil numbers in a healthy setting, we studied whether eosinophil blood counts correlate with their activation status and their responsiveness to formyl peptides in a cohort of long-distance runners participating in a mass-participation trail run (22, 29 or 43 km). The study was approved by medical research ethics committee Oost-Nederland (NL79864.091.22). After written informed was obtained, venous blood samples were collected from 35 athletes before, directly after and 24 hours after exercise. The eosinophil activation status was assessed by combining automated flow cytometry with a 5-dimensional algorithm-based gating.An acute leukocytosis with eosinopenia was present directly post-exercise, which is in agreement with previous research. These numbers normalized 24 hours after exercise (figure 1A, 1C ). Compared to before exercise, eosinophils showed a more activated phenotype (increased CD11b and decreased CD62L) directly after exercise which also normalized within 24 hours. In marked contrast to acute inflammation, such as caused by SARS-CoV2 infection, this eosinopenia directly after exercise did not lead to refractoriness to fNLF-stimulation. However, after the normalization of eosinophil counts 24 hours after exercise, the eosinophils were refractory for activation by fNLF (figure 1B, 1C ). This clearly showed a complete dissociation between blood eosinophil numbers and their relative activation status.Our results illustrate that the eosinophil blood compartment is not adequately characterized by solely counting cell numbers (‘quantity’) as normalized numbers do not necessarily reflect normalization of their activation status (‘quality’). This finding is not limited to measuring the state of type II immunity in eosinophilic disease, but probably also applies to other infectious/inflammatory conditions and to non-pathological settings. Our data call for a re-evaluation of using blood eosinophil counts as an adequate representation of the eosinophil compartment’s state. Until recently, determining the activation status of the eosinophil compartment was complicated by ex vivo artifacts already starting at the moment of venipuncture. Now with the availability of fast, automated, point-of-care flow cytometry, it is feasible to measure both the quantity and quality of eosinophils in a wide scope of health and disease settings.

Identifying candidate genes associated with resistance to northern leaf blight (NLB) will greatly enhance maize breeding programs aiming at reducing maize grain yield losses caused by NLB. In this study, a multi-parental population (MPP) was constructed consisting of four recombined inbred line (RIL) subpopulations, all sharing a common parent Ye107, for GWAS and linkage analysis. The results revealed the detection of a significant SNP, 5-49193921, from a tropical maize inbred line YML226. This SNP was found to be associated with the gene Zm00001d014471, which encodes a pentatricopeptide repeat (PPR-like) superfamily protein. Furthermore, gene expression analysis showed a positive correlation between the expression of Zm00001d014471 and NLB resistance. Notably, the F 1 generation of YML226 × Ye107 contained the largest number of specific SNPs within the genic region, suggesting that its abundant genetic variation might contribute to its high NLB resistance. Furthermore, there was a specific nonsynonymous SNP (C to T) causing a nucleotide change at position 235, leading to an alteration of an amino acid, which resulted in the modification of a motif in the PPR protein. Our results revealed that tropical maize germplasm YML226 could serve an important genetic resource for NLB resistance. Additionally, previous studies have shown that YML226 is an exceptional elite line derived from CATETO germplasm, exhibiting a higher positive general combining ability for grain yield. Therefore, YML226 holds great promise for the breeding of NLB-resistant maize cultivars in the future.