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Introduction: Early prediction of abrocitinib efficacy in atopic dermatitis (AD) could help identify candidates for an early dose increase. A predictive model determined week 12 efficacy based on week 4 responses in patients receiving abrocitinib 100 mg/day and assessed the effect of an abrocitinib dose increase on platelet counts. Methods: Analysis included the phase 3 trials JADE MONO-1 (NCT03349060), MONO-2 (NCT03575871), COMPARE (NCT03720470), and TEEN (NCT03796676). For platelet counts and simulations, a phase 2 psoriasis trial (NCT02201524) and phase 2b (NCT02780167) and phase 3 (MONO-1, MONO-2, and REGIMEN (NCT03627767)) abrocitinib trials were pooled. A training-and-validation framework assessed potential predictors of response at week 4: score and score change from baseline in the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (PP-NRS), and percentage change from baseline in EASI. The dependent variables at week 12 were ≥ 75% improvement in EASI (EASI-75) and IGA score of 0 (clear) or 1 (almost clear) and ≥ 2-point improvement from baseline. The probability of each variable to predict week 12 EASI-75 and IGA responses was calculated. Results: In the training cohort (n = 453), 72% of the ≥ 50% improvement in EASI (EASI-50) at week 4 responders and 16% of the nonresponders with abrocitinib 100 mg achieved EASI-75 at week 12; 48% and 6% of the week 4 EASI-50 responders and nonresponders, respectively, achieved week 12 IGA response. Similar results occurred with week 4 IGA = 2, ≥ 4-point improvement from baseline in PP-NRS, or EASI = 8 responders/nonresponders. Platelet counts after an abrocitinib dose increase from 100 to 200 mg were similar to those seen with continuous dosing with abrocitinib 100 mg or 200 mg. Conclusion: Achieving week 4 clinical responses with abrocitinib 100 mg may be useful in predicting week 12 responses. Week 4 nonresponders may benefit from a dose increase to abrocitinib 200 mg, and those that receive this dose increase are likely to achieve treatment success at week 12, with no significant impact on platelet count recovery. Video abstract available for this article. Clinical Trial Registration: NCT03349060, NCT03575871, NCT03720470, NCT03796676, NCT02201524, NCT02780167 and NCT03627767. Plain Language Summary: Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis. Abrocitinib tablets are available in two doses (100 and 200 mg) and are taken by mouth once daily. Some people with atopic dermatitis who are taking abrocitinib 100 mg may need to increase the dose to 200 mg to get adequate symptom relief. We studied whether people with atopic dermatitis who did or did not experience clear skin or itch relief after taking abrocitinib 100 mg for 4 weeks are likely or not likely to experience relief after 12 weeks of treatment. We also defined the level of response after 4 weeks of treatment that best differentiates people who did or did not experience symptom relief, and we identified who might benefit from increasing the abrocitinib dose from 100 to 200 mg. We found that people with atopic dermatitis who had symptom relief after 4 weeks of abrocitinib 100 mg treatment were much more likely to have greater relief after 12 weeks, and people who did not achieve symptom relief after 4 weeks may benefit from a dose increase at week 4. Some people who receive abrocitinib 200 mg may have a temporary decrease in the number of certain blood cells called platelets at week 4, but platelets return to near-normal levels by week 12. This analysis showed that increasing the abrocitinib dose from 100 to 200 mg at week 4 did not seem to affect the platelet numbers after week 4. 5jM1pAZWXrzNQJZKGQNXfy Video abstract (MP4 174529 KB) [ABSTRACT FROM AUTHOR]

Objective: To explore peripheral blood indicators that may serve as early indicators for multidrug‐resistant bacteria (MDR) infections in this demographic, with the goal of providing reference suggestions for the clinical prevention of MDR infections in elderly inpatients. Methods: Clinical data of patients were divided into the MDR‐infected group (n = 488) and the MDR‐uninfected group (n = 233) according to the results of drug sensitivity experiments, risk factors for MDR infection, and peripheral blood indicators related to MDR infections were analyzed using univariate and multivariate logistic regression in conjunction with the construction of a Chi‐squared automatic interaction detector (CHAID) decision tree model, considering statistical significance at p <.05. Results: Of 721 patients, 488 multidrug‐resistant strains were identified. Among them, with Staphylococcus spp. the most prevalent in 148 strains. The most frequent detection of MDR occurred in puncture fluid samples (167 cases). Univariate and multivariate regression analyses revealed that prolonged hospitalization, use of antibiotics preadmission, duration of antibiotics, invasive procedures or recent surgery, and coexisting lung disease were independent risk factors for contracting MDR. Subsequent analysis comparing the aforementioned influences with peripheral blood cells revealed associations between the number of antibiotic treatment days and increased neutrophil‐to‐lymphocyte ratio (NLR), platelet count‐to‐lymphocyte ratio (PLR), neutrophils, decreased lymphocytes, and increased eosinophils; preadmission antibiotic use correlated with increased PLR, NLR, neutrophils, and decreased lymphocytes; and invasive manipulation or surgery correlated with increased PLR and NLR. Conclusions: Elevated NLR, PLR, neutrophils, lowered lymphocytes, and eosinophils may serve as early indicators of MDR infections in elderly hospitalized patients. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma (KS) is a cancer originating from the endothelial cells of blood and lymphatic vessels. It develops multifocally as a result of pathological vascular hyperplasia. There are four forms of the disease: classic, endemic, iatrogenic, and epidemic. The treatment of Kaposi’s sarcoma depends on the clinical form, stage of advancement, and the immunological condition of the patient. The article presents the case of an 82-year-old patient from the Dermatology Department of the Provincial Hospital in Elblag diagnosed with Kaposi’s sarcoma with bullous lesions. [ABSTRACT FROM AUTHOR]

Background: Vitamin C (VitC) is a widely used antioxidant in poultry production. However, there is some ambiguity about the effects of VitC in reducing oxidative stress in poultry when they are under heat stress. Therefore, the objective of this study was to investigate the effects of VitC on reducing oxidative stress and nitric oxide (NO) formation which affects the viability of the broiler finisher blood cells (BFBC). Methods: BFBC were maintained at temperature at 41oC and the temperature increasing from 41oC to 45oC. At 41oC to 45oC, BFBC supplemented with VitC solution at concentrations of 0, 25, 50 and 75 µmol. Then, total antioxidant power (FRAP), malondialdehyde (MDA), hydrogen peroxide (H2O2 ), NO in supernatant and the viability of BFBC were measured. Result: It was found that MDA and NO levels were increased at high ambient temperature (P<0.05). At the same time, the viability of BFBC was decreased (P<0.05). Vitamin C at the concentration of 50 µmol could reduce MDA and NO better than at other concentrations (P<0.05) and increased the viability of BFBC (P<0.05). This phenomenon indicated that VitC reduced oxidative stress and NO levels, which were important factors for BFBC viability at high ambient temperature [ABSTRACT FROM AUTHOR]

Problem: Adenomyosis (AM) is associated with immune response and inflammation. However, the role of T cell subsets in AM development has not been thoroughly understood. Method of Study: Patients with focal or diffuse AM were recruited. Serum cytokines were quantified by enzyme‐linked immunosorbent assay (ELISA). Different T cell subsets in the blood and ectopic endometrium were determined by flow cytometry. Results: Serum interleukin‐6 (IL‐6) and macrophage‐colony‐stimulating factor (GM‐CSF) were increased in patients with focal or diffuse AM before focused ultrasound ablation surgery (FUAS), but not after FUAS. Compared with the healthy control, the frequencies of CD8+ interferon‐gamma (IFN‐γ)‐expressing cytotoxic T lymphocytes (CTLs), interleukin‐17A (IL‐17A)‐expressing Tc17 cells, CD4+ T helper 1 (Th1) cells, and GM‐CSF‐expressing T helper (ThGM) cells were up‐regulated in the blood of patients with AM, especially those with diffuse AM. However, these changes were eradicated after FUAS. Meanwhile, the frequencies of these T cell subsets were positively correlated with the CA‐125 level. Furthermore, these T cell subsets were also increased in ectopic endometrium. Conclusions: Our study delineates for the first time the presence of CTLs, Tc17 cells, Th1, and ThGM cells in the blood and ectopic endometrium in AM. The results imply that T cell response might impact AM development. [ABSTRACT FROM AUTHOR]

The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2 -overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis. Synopsis: The molecular mechanisms controlling the response of hematopoietic stem cells (HSCs) to insults remain poorly defined. Here, genetic data support a critical role of chromatin modifier Hmga2 in stress-induced regeneration of the adult murine blood system. Conditional depletion of Hmga2 does not affect steady-state hematopoiesis but impairs HSC response to 5-fluorouracil (5-FU) in adult mice. Under stress, CK2 kinase phosphorylates Hmga2 in TNF-α-dependent manner, promoting its chromatin binding and repression of inflammatory genes by transcription factor Rfx5. The identified stress-induced Hmga2 gene signature is activated in hematopoietic stem and progenitor cells of human myelodysplastic syndrome patients. A TNF-a/CK2/phospho-HMGA2 axis controls chromatin accessibility, transcription, and expansion of blood stem cells in response to stress. [ABSTRACT FROM AUTHOR]

Blood cancer is caused because of changes in DNA within blood cells and it's not genetic. The efficient and early detection of blood cancer can help in curing it. We have designed a blood cancer sensor which is detecting it fast and efficiently. The double split ring resonator gold metasurface is placed on graphene material and backed by MgF2 substrate which makes the detection fast and effective. The overall sensitivity, FOM, Q-factor and DL are 3571 nm/RIU, 714 RIU−1 value, 322 and 0.00933 RIU for the designed sensor respectively. The sensitivity is optimized by changing the different parameters like length, height of resonator, and height of MgF2 substrate. The designed sensor also shows tunable behavior with variation in graphene potential. The electric field analysis of the sensor matches well with the obtained absorption results of the blood cancer sensor. The negative values of permittivity and permeability in the investigated wavelength range give validation of the metasurface effect in the proposed sensor. The highly efficient proposed blood cancer sensor can be used for fast-detecting biomedical devices. [ABSTRACT FROM AUTHOR]

For acquiring an ideal sorbent for hemoperfusion, three crucial problems should be addressed: 1. The gap between the stacked sorbents should be larger than the blood cells, around 600 μm, for a continuous pass-through of blood in a hemoperfusion device. 2. The hemoperfusion device should maintain at least a 190 ml/min flow rate. 3. Specific binding on the sorbents is required to absorb the harmful agent in blood. In this research we developed a low-surfactant emulsification technique to prepare physically crosslinked cellulose microspheres (CMs). The particle size of the CMs could be tuned from 150 μm to 1000 μm. Three dehydration methods also regulated the mechanical properties of the CMs. The perfusion column stacked by physically crosslinked CMs, after being treated by an ethanol bath, could withstand pressure induced by a flow rate of 190 ml/min. The adsorption processes of hydrophobic alkyl carbon chain (C18) modified CMs for bilirubin conformed to the Langmuir isothermal adsorption model, which indicated that the bilirubin adsorption by C18 grafted CMs mainly relied on the interaction between C18 and bilirubin. In summary, a facile, scalable and low-surfactant fabrication strategy was developed to synthesize regenerated cellulose microspheres with high strength and porosity as a promising absorbent for hemoperfusion. [ABSTRACT FROM AUTHOR]

Background and Purpose: RO7502175 is an afucosylated antibody designed to eliminate C–C motif chemokine receptor 8 (CCR8)+ Treg cells in the tumour microenvironment through enhanced antibody‐dependent cellular cytotoxicity (ADCC). Experimental Approach: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first‐in‐human (FiH) dosing strategy and clinical development in solid tumour indications. Key Results: RO7502175 demonstrated selective ADCC against human CCR8+ Treg cells from dissociated tumours in vitro. In cynomolgus monkeys, RO7502175 exhibited a biphasic concentration–time profile consistent with immunoglobulin G1 (IgG1) antibodies, reduced CCR8+ Treg cells in the blood, induced minimal and transient cytokine secretion, and was well tolerated with a no‐observed‐adverse‐effect level (NOAEL) of 100 mg·kg−1. Moreover, RO7502175 caused minimal cytokine release from peripheral blood mononuclear cells (PBMCs) in vitro. A quantitative model was developed to capture surrogate anti‐murine CCR8 antibody PK/PD and tumour dynamics in mice and RO7502175 PK/PD in cynomolgus monkeys. Subsequently, the model was used to project RO7502175 human PK and receptor occupancy (RO) in patients. Because traditional approaches resulted in a low FiH dose for this molecule, even with its superior preclinical safety profile, an integrated approach based on the totality of preclinical data and modelling insights was used for starting dose selection. Conclusion and Implications: This work demonstrates a translational research strategy for collecting and utilizing relevant nonclinical data, developing a mechanistic PK/PD model and using a comprehensive approach to inform clinical study design for RO7502175. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a heterogeneous chronic psychiatric disorder influenced by genetic and environmental factors. Environmental factors can alter epigenetic marks, which regulate gene expression and cause an array of systemic changes. Several studies have demonstrated the association of epigenetic modulations in schizophrenia, which can influence clinical course, symptoms, and even treatment. Based on this, we have examined the global DNA methylation patterns, namely the 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC); and the global RNA modification N6-methyladenosine (m6A) RNA methylation status in peripheral blood cells. First-Episode Psychosis (FEP) patients who were diagnosed with Schizophrenia (SCZ) and undergoing treatment were stratified as Treatment-Responsive (TR) and Treatment-Non-Responsive (TNR). Age- and sex-matched healthy subjects served as controls. Results: The methylation pattern of 5mC and 5hmC showed significant increases in patients in comparison to controls. Further, when patients were classified based on their response to treatment, there was a statistically significant increase in methylation patterns in the treatment non-responder group. 5fC and m6A levels did not show any statistical significance across the groups. Further, gender-based stratification did not yield any significant difference for the markers. Conclusion: The study highlights the increased global methylation pattern in SCZ patients and a significant difference between the TR versus TNR groups. Global 5mC and 5hmC epigenetic marks suggest their potential roles in schizophrenia pathology, and also in the treatment response to antipsychotics. Since not many studies were available on the treatment response, further validation and the use of more sensitive techniques to study methylation status could unravel the potential of these epigenetic modifications as biomarkers for SCZ as well as distinguishing the antipsychotic treatment response in patients. [ABSTRACT FROM AUTHOR]

This study presents a cancer diagnostics method through the development of a graphitic carbon nitride (g-C 3 N 4)-based electrochemical sensor for detecting circulating tumor cells (CTCs) in blood. Utilizing the unique properties of g-C 3 N 4 nanosheets combined with gold nanoparticles functionalized with DNA aptamers, the sensor exhibits remarkable sensitivity and selectivity in CTC detection. The aptamers specifically target cell surface biomarkers, enabling the precise capture and quantification of CTCs. The sensor's detection limit is an impressive 5 cells/mL, with a broad detection range from 10 to 105 cells/mL. This high-performance sensing platform not only achieves rapid and accurate quantification of CTCs but also demonstrates robustness against interference from other cell types, making it highly suitable for clinical applications. The optimized conditions for aptamer-functionalized nanoparticle concentration and incubation time ensure the sensor's efficacy, as validated in spiked blood samples. This work provides a practical and efficient approach for non-invasive cancer diagnostics, offering significant improvements over existing methods in terms of simplicity, sensitivity, and specificity for early detection and monitoring of cancer progression. [ABSTRACT FROM AUTHOR]

Non-neoplastic bone marrow disorders are main causes of non-regenerative anemia in dogs. Despite the high incidence of the diseases, their molecular pathophysiology has not been elucidated. We previously reported that Miniature Dachshund (MD) was a predisposed breed to be diagnosed with non-neoplastic bone marrow disorders in Japan, and immunosuppressive treatment-resistant MDs showed higher number of platelets and morphological abnormalities in peripheral blood cells. These data implied that treatment-resistant MDs might possess distinct pathophysiological features from treatment-responsive MDs. Therefore, we conducted transcriptomic analysis of bone marrow specimens to investigate the pathophysiology of treatmentresistant MDs. Transcriptomic analysis comparing treatment-resistant MDs and healthy control dogs identified 179 differentially expressed genes (DEGs). Pathway analysis using these DEGs showed that "Wnt signaling pathway" was a significantly enriched pathway. We further examined the expression levels of DEGs associated with Wnt signaling pathway and confirmed the upregulation of AXIN2 and CCND2 and the downregulation of SFRP2 in treatment-resistant MDs compared with treatmentresponsive MDs and healthy control dogs. This alteration implied the activation of Wnt signaling pathway in treatment-resistant MDs. The activation of Wnt signaling pathway has been reported in human patients with myelodysplastic syndrome (MDS), which is characterized by dysplastic features of blood cells. Therefore, the results of this study implied that treatment-resistant MDs have distinct molecular pathological features from treatment-responsive MDs and the pathophysiology of treatment-resistant MDs might be similar to that of human MDS patients. [ABSTRACT FROM AUTHOR]

Lymph node stromal cells (LNSCs) are an often overlooked component of the immune system but play a crucial role in maintaining tissue homeostasis and orchestrating immune responses. Our understanding of the functions these cells serve in the context of bacterial infections remains limited. We previously showed that Listeria monocytogenes , a facultative intracellular foodborne bacterial pathogen, must replicate within an as-yet-unidentified cell type in the mesenteric lymph node (MLN) to spread systemically. Here, we show that L. monocytogenes could invade, escape from the vacuole, replicate exponentially, and induce a type I interferon response in the cytosol of 2 LNSC populations infected in vitro, fibroblastic reticular cells (FRCs) and blood endothelial cells (BECs). Infected FRCs and BECs also produced a significant chemokine and proinflammatory cytokine response after in vitro infection. Flow cytometric analysis confirmed that GFP+ L. monocytogenes were associated with a small percentage of MLN stromal cells in vivo following foodborne infection of mice. Using fluorescent microscopy, we showed that these cell-associated bacteria were intracellular L. monocytogenes and that the number of infected FRCs and BECs changed over the course of a 3-day infection in mice. Ex vivo culturing of these infected LNSC populations revealed viable, replicating bacteria that grew on agar plates. These results highlight the unexplored potential of FRCs and BECs to serve as suitable growth niches for L. monocytogenes during foodborne infection and to contribute to the proinflammatory environment within the MLN that promotes clearance of listeriosis. [ABSTRACT FROM AUTHOR]

C-mannosylation is a post-translational modification that occurs intracellularly in the endoplasmic reticulum. In humans, biosynthesis of C-mannosylation in proteins containing thrombospondin type 1 repeat is catalyzed by the DPY19 family; nonetheless, biological functions of protein C-mannosylation are not yet fully understood, especially in tumor progression. Vasculogenic mimicry (VM) is the formation of fluid-conducting channels by highly invasive and genetically deregulated tumor cells, enabling the tumors to form matrix-embedded vasculogenic structures, containing plasma and blood cells to meet the metabolic demands of rapidly growing tumors. In this study, we focused on DPY19L3, a C-mannosyltransferase, and aimed to unravel its role in VM. Knockout of DPY19L3 inhibited the formation of VM in HT1080 human fibrosarcoma cells. Re-expression of wild-type DPY19L3 recovered VM formation; however, DPY19L3 isoform2, an enzymatic activity-defect mutant, did not restore it, suggesting that the C-mannosyltransferase activity of DPY19L3 is crucial to its function. Furthermore, the knockdown of DPY19L3 in MDA-MB-231 breast cancer cells hindered its network formation ability. Altogether, our findings suggest that DPY19L3 is required for VM formation and stipulate the relevance of C-mannosylation in oncogenesis. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (GO), a CD33-targeting antibody drug conjugate, previously showed longer relapse-free survival when combined with induction chemotherapy in patients with favorable-risk acute myeloid leukemia (AML). In this patient population, characterized by lower relapse risk as compared to other ELN risk groups, autologous stem cell transplantation (ASCT) can be used as consolidation strategy. However, there are limited data on the impact of GO on the peripheral blood stem cell (PBSC) mobilization potential. We therefore retrospectively analyzed data from 54 AML patients with favorable-risk AML treated with (n = 17) or without (n = 37) GO during induction treatment. We observed no significant differences in the PBSC mobilization rate between patients treated with vs. without GO. The mobilization success in a first attempt directly following cycle 2 was 65% vs. 70% (p = 0.92); and the mobilization success in a subsequent second attempt after hematologic recovery and repeated stimulation procedure was 24% vs. 19% (p = 0.56). No significant impact on treatment outcome in terms of EFS (p = 0.31) or OS (p = 0.99) was observed. Thus, our results suggest that the addition of GO to induction regimens does not negatively impact PBSC mobilization in favorable-risk AML patients. To our best knowledge, this is the first study comparing the stem cell mobilization potential in favorable-risk AML patients treated with vs. without GO. [ABSTRACT FROM AUTHOR]

Background: Mean corpuscular hemoglobin concentration (MCHC) is one of the parameters detected by blood cell analyzers, often used together with mean corpuscular volume (MCV) and mean corpuscular hemoglobin content (MCH) as diagnostic indicators for anemia classification. It has important clinical value in early detection of the cause of anemia and the underlying etiology of anemia. Therefore, the accuracy of MCHC results is of great significance for the diagnosis and treatment of diseases. Methods: We reported two cases of false elevation of MCHC. Considering the possibility of cold agglutination and lipid blood interference detection, we used 37℃ water bath and plasma exchange to correct for interference on the sample. Results: After correcting the interference, MCHC returned to normal, consistent with the patient's disease status. Therefore, the two cases of abnormal elevation of MCHC are considered to be pseudo elevation caused by interference. Conclusions: For specimens with abnormally elevated MCHC levels, experimenters should first analyze possible interfering factors and choose effective methods to correct different interferences, providing accurate testing reports for doctors and patients. [ABSTRACT FROM AUTHOR]

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Nanomaterials have been extensively used in the biomedical field due to their unique physical and chemical properties. They promise wide applications in the diagnosis, prevention, and treatment of diseases. Nanodrugs are generally transported to target tissues or organs by coupling targeting molecules or enhanced permeability and retention effect (EPR) passively. As intravenous injection is the most common means of administration of nanomedicine, the transport process inevitably involves the interactions between nanoparticles (NPs) and blood cells. Platelets are known to not only play a critical role in normal coagulation by performing adhesion, aggregation, release, and contraction functions, but also be associated with pathological thrombosis, tumor metastasis, inflammation, and immune reactions, making it necessary to investigate the effects of NPs on platelet function during transport, particularly the way in which their physical and chemical properties determine their interaction with platelets and the underlying mechanisms by which they activate and induce platelet aggregation. However, such data are lacking. This review is intended to summarize the effects of NPs on platelet activation, aggregation, release, and apoptosis, as well as their effects on membrane proteins and morphology in order to shed light on such key issues as how to reduce their adverse reactions in the blood system, which should be taken into consideration in NP engineering. [ABSTRACT FROM AUTHOR]

The present study was conducted on the blood cells of thirty domestic fowls, guinea fowls and pigeons. Ten birds were taken from each species. Basophils in all the three species were positive for mucopolysaccharides. The reactivity in guinea fowls was strong, moderate in pigeons and weak in domestic fowls. Heterophils showed strong reactivity in guinea fowls, moderate in pigeons and weakest reaction in fowls for glycogen when stained with PAS stain. Eosinophils of guinea fowls showed strongest and moderate reactivity in fowls, while weakest reactivity was observed in pigeons when blood smears were stained with Sudan Black B stain. Leucocytes showed negative reaction for mucopolysaccharide, glycogen and lipid in domestic fowls, guinea fowls and pigeons. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to examine the effect of hydroalcoholic extract of Psidium guajava plant on bone marrow cells in rats and it will be extended to humans. Guava plant leaves were collected from Chabahar region in Sistan and Baluchistan province and dried. 40 adult male rats were assigned to one control group and three experimental groups (subjects that were administeredhydroalcoholic extract of P. guajava leaves with respective doses of 3000 mg/kg, 4000 mg/kg, or 5000 mg/kg, for 3 months, once daily). Following the intervention period, blood was taken from the heart and bone marrow was taken from the femur. Several parameters such as cell blood count, hemoglobin, and hematocrit, were examined in the blood sample. Also, in the bone marrow sample, a relative count was performed on five hundred bone marrow cells and the ratio of myeloid to erythroid was determined in both control and experimental groups. The results of this study indicated that the hydroalcoholic extract somewhat increased white blood cells and red blood cells, but no significant change was observed. The result of the study revealed the positive effects of guava leaf extract may be due to flavonoids, quercetin and triterpenes, which strong antioxidants that can prevent damage are caused by free radicals destroying cells. This study shows that guava leaf extract can have a positive effect on hematological parameters, as well as the lack of mutagenicity and cytotoxicity in high doses of this plant extract rather reflects its safe use in traditional medicine. Therefore, it is recommended that guava leaf extract be considered as a complementary and alternative treatment for many diseases, including the treatment of anemia.

Abstract Non-coding RNA expression has shown to have cell type-specificity. The regulatory characteristics of these molecules are impacted by changes in their expression levels. We performed next-generation sequencing and examined small RNA-seq data obtained from 6 different types of blood cells separated by fluorescence-activated cell sorting of severe COVID−19 patients and healthy control donors. In addition to examining the behavior of piRNA in the blood cells of severe SARS-CoV−2 infected patients, our aim was to present a distinct piRNA differential expression portrait for each separate cell type. We observed that depending on the type of cell, different sorted control cells (erythrocytes, monocytes, lymphocytes, eosinophils, basophils, and neutrophils) have altering piRNA expression patterns. After analyzing the expression of piRNAs in each set of sorted cells from patients with severe COVID−19, we observed 3 significantly elevated piRNAs - piR−33,123, piR−34,765, piR−43,768 and 9 downregulated piRNAs in erythrocytes. In lymphocytes, all 19 piRNAs were upregulated. Monocytes were presented with a larger amount of statistically significant piRNA, 5 upregulated (piR−49039 piR−31623, piR−37213, piR−44721, piR−44720) and 35 downregulated. It has been previously shown that piR−31,623 has been associated with respiratory syncytial virus infection, and taking in account the major role of piRNA in transposon silencing, we presume that the differential expression patterns which we observed could be a signal of indirect antiviral activity or a specific antiviral cell state. Additionally, in lymphocytes, all 19 piRNAs were upregulated.

Background: Examination of blood smears and various hematologic parameters is the first step in assessment of hematologic function and diagnosis of possible underlying diseases. The aim of this study was to identify artefacts in stored red blood cells and classify the occurrence of such alterations according to the age of the stored sample. This studyalso aimed to note the changes in platelet count dispatched by automated hematology coulter in such stored blood samples. Material and Methods: A prospective cross sectional study was conducted from the EDTA anticoagulated blood samples of 100 patients received in the department of Pathology after receiving ethical approval from the institutional review committee. All the samples were analyzed in 4 occasions i.e. within 2 hours, at 24 hours, at 48 hours and at 96 hours. Analysis was carried out by Sysmex 5 part analyzer for platelet counts and the Leishman stained blood films were examined to note changes in the erythroctyte morphology. Results: There was alterationsin platelet counts in 22% cases between 2-hour samples and other samples. The red blood cell morphology was not different among 2 hours samples and 24 hours sample. However, the red blood cell morphology was altered in 48 hours samples and 96 hours samples. Conclusion: Storage of EDTA anticoagulated blood even upon refrigeration can cause changes in platelet counts as well as morphology of red blood cells. Changes in red blood cells are not significant till 24 hours while the platelet counts may alter within 24 hours.

Aims: Transfusion after primary total hip arthroplasty (THA) has become rare, and identification of causative factors allows preventive measures. The aim of this study was to determine patient-specific factors that increase the risk of needing a blood transfusion. Methods: All patients who underwent elective THA were analyzed retrospectively in this single-centre study from 2020 to 2021. A total of 2,892 patients were included. Transfusion-related parameters were evaluated. A multiple logistic regression was performed to determine whether age, BMI, American Society of Anesthesiologists (ASA) grade, sex, or preoperative haemoglobin (Hb) could predict the need for transfusion within the examined patient population. Results: The overall transfusion rate was 1.2%. Compared to the group of patients without blood transfusion, the transfused group was on average older (aged 73.8 years (SD 9.7) vs 68.6 years (SD 10.1); p = 0.020) and was mostly female (p = 0.003), but showed no significant differences in terms of BMI (28.3 kg/m2 (SD 5.9) vs 28.7 kg/m2 (SD 5.2); p = 0.720) or ASA grade (2.2 (SD 0.5) vs 2.1 (SD 0.4); p = 0.378). The regression model identified a cutoff Hb level of < 7.6 mmol/l (< 12.2 g/dl), aged > 73 years, and a BMI of 35.4 kg/m² or higher as the three most reliable predictors associated with postoperative transfusion in THA. Conclusion: The possibility of transfusion is predictable based on preoperatively available parameters. The proposed thresholds for preoperative Hb level, age, and BMI can help identify patients and take preventive measures if necessary. Cite this article: Bone Jt Open 2024;5(7):560–564.

The advent of single cell transposase-accessible chromatin sequencing (scATAC-seq) technology enables us to explore the genomic characteristics and chromatin accessibility of blood cells at the single-cell level. To fully make sense of the roles and regulatory complexities of blood cells, it is critical to collect and analyze these rapidly accumulating scATAC-seq datasets at a system level. Here, we present scBlood (https://bio.liclab.net/scBlood/), a comprehensive single-cell accessible chromatin database of blood cells. The current version of scBlood catalogs 770,907 blood cells and 452,247 non-blood cells from ∼400 high-quality scATAC-seq samples covering 30 tissues and 21 disease types. All data hosted on scBlood have undergone preprocessing from raw fastq files and multiple standards of quality control. Furthermore, we conducted comprehensive downstream analyses, including multi-sample integration analysis, cell clustering and annotation, differential chromatin accessibility analysis, functional enrichment analysis, co-accessibility analysis, gene activity score calculation, and transcription factor (TF) enrichment analysis. In summary, scBlood provides a user-friendly interface for searching, browsing, analyzing, visualizing, and downloading scATAC-seq data of interest. This platform facilitates insights into the functions and regulatory mechanisms of blood cells, as well as their involvement in blood-related diseases.

Background: Immunotherapy provided significant survival benefits for recurrent and metastatic patients with head and neck cancer. These improvements could not be reproduced in patients treated with curative-intent chemoradiotherapy (CRT) and the optimal radio-immunotherapy (RIT) concepts have yet to be designed. Exploration and analysis of the pre-therapeutic immune status of these patients and the changes occurring during the treatment course could be crucial in rationally designing future combined treatments. Methods: Blood samples were collected from a cohort of 25 head and neck cancer patients treated with curative-intended (C)-RT prior to therapy, after the first week of treatment, and three months after treatment completion. Peripheral blood mononuclear cells (PBMCs) or all nucleated blood cells were isolated and analyzed via flow cytometry. Results: At baseline, patients showed reduced monocyte and lymphocyte counts compared to healthy individuals. Although overall CD8+ T-cell frequencies were reduced, the proportion of memory subsets were increased in patients. Radiotherapy (RT) treatment led to a further increase in CD8+ effector memory T-cells. Among myeloid populations, tumor-promoting subsets became less abundant after RT, in favor of pro-inflammatory cells. Conclusion: The present study prospectively demonstrated a complex interplay and distinct longitudinal changes in the composition of lymphocytic and myeloid populations during curative (C)-RT of head and neck cancer. Further validation of this method in a larger cohort could allow for better treatment guidance and tailored incorporation of immunotherapies (IT) in the future. [ABSTRACT FROM AUTHOR]

[Display omitted] In emergencies, uncontrolled severe bleeding can result in undesired complications and even death of the injured. Designing advanced hemostatic agents is a potential solution for emergency hemostasis, yet it remains challenging to realize the persistent adhesion in a wet wound environment. In this study, based on dynamic reversible Schiff base bond and photo-initiated double-bond polymerization, a novel injectable hemostatic hydrogel (L -COC) consisting of methacrylated carboxymethyl chitosan (CMCSMA), oxidized konjac glucomannan (OKGM) and (+)-catechin hydrate (CH) was synthesized for emergency hemostasis. To our delight, the incorporated CH imparted enhanced blood procoagulantion to the L -COC hydrogel by intensifying the hydrogel-red blood cell interactions. As a result, the hemostatic effect of the engineered L -COC hydrogel was significantly superior to that of fluid gelatin SurgifloTM for liver bleeding wounds in rats (Blood loss: 0.62 ± 0.11 g (L -COC), 0.90 ± 0.08 g (SurgifloTM); hemostasis time: 69.0 ± 2.9 s (L -COC), 84.0 ± 2.2 s (SurgifloTM)). With the favorable antioxidant and antibacterial activities, as well as multifunctional properties, the bio-adhesive L -COC hydrogel and the underlying design principles may facilitate further development of practical hemostatic hydrogels. [ABSTRACT FROM AUTHOR]

Major depression (MD) is recurrent and devastating mental disease with a high worldwide prevalence. Mounting evidence suggests neuroinflammation triggers cellular immune dysregulation, characterized by increased proportions of circulating monocytes, and T helper 17 cells and proinflammatory cytokines, thereby increasing susceptibility to MD. However, there is ambiguity in the findings of clinical studies that investigate CD4+ T regulatory (Treg) cells in MD. The proportion of CD4+ Treg cell from blood mononuclear cells was examined using flow cytometry in healthy controls (HCs: n = 96) and patients with first (FEMD: n = 62) or recurrent (RMD: n = 41) disease episodes of MD at baseline (T0; hospital admission) and after a two-week antidepressant treatment (T14). All participants underwent comprehensive neuropsychological assessments. The initial scores on emotional assessments in patients with MD significantly differed from those of HCs. Both FEMD and RMD patients exhibited a significant decrease in CD4+ Treg cell proportion at baseline compared to HCs. Treg cell proportion rose significantly from T0 to T14 in FEMD patients, who responded to antidepressant therapy, whereas no significant changes were observed in FEMD patients in non-response as well as RMD patients. The improvement of 24-item Hamilton Depression Scale was correlate with changes of Treg cell proportion from T0 to T14 in FEMD patients in response, and the change in Treg cell proportion over a 14-day period exhibited an AUC curve of 0.710. A decrease in the proportion of CD4+ Treg cells points towards immune system abnormalities in patients with MD. Furthermore, our finding suggests that the immune activation state varies across different stages of depression. • Regulatory T cell proportion was decreased in major depression patients • Regulatory T cells may involve in early depression treatment • Regulatory T cells indicate distinct immune states at various stages of depression [ABSTRACT FROM AUTHOR]

Immune-inflammatory mediators influence numerous immune and inflammatory pathways, elevating the likelihood of depression. The systemic immune-inflammation index (SII) emerges as an innovative prognostic indicator, integrating various peripheral blood immune cell subpopulations, specifically neutrophils, platelets, and lymphocytes. This exploratory study aims to examine the correlation between SII and depression. Data from the 2005–2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Depression was diagnosed with a Patient Health Questionnaire score of 10 or higher. The relationship between log2-SII and depression incidence was analyzed using a restricted cubic spline (RCS). Logistic regression was employed to calculate the odds ratio of depression concerning log2-SII. In cases of non-linearity, piecewise linear models with change points were applied to assess the associations in both the overall population and specific subgroups. Additionally, subgroup analyses were conducted to determine the applicability of the findings to particular populations. A total of 42,133 participants were included in the study, comprising 49.32 % men and 50.68 % women, with an average age of 47.02 ± 17.45 years. RCS analysis demonstrated a J-shaped non-linear relationship between log2-SII and depression incidence. When log2-SII was ≥8.50, SII showed a positive association with depression incidence, even after adjusting for covariates. Additionally, each unit increase in log2-SII corresponded to an 18 % rise in depression incidence (OR = 1.18, 95 % CI: 1.10–1.27). Subgroup analysis further revealed that the association between SII and depression incidence varied across different populations. Due to the cross-sectional nature of NHANES, causality or long-term implications cannot be inferred. Further research is needed to ascertain if a longitudinal relationship exists between SII and depression. Our findings suggest a significant and complex non-linear association between SII and depression. However, further basic and prospective studies are necessary to explore SII's impact on depression and clarify its underlying mechanisms. Additionally, these studies will provide a foundation for personalized interventions targeting the immune-inflammatory processes in patients with depression and elevated SII. • Systemic immune-inflammation index was associated with depression in a complicated non-linear manner. • High systemic immune-inflammation index was associated with high depression incidence. • Immune-inflammatory mediators may increase the risk of depression. [ABSTRACT FROM AUTHOR]

Abstract The joint impact of tadalafil (Cilais) as a pharmaceutical residue and microplastics on fish is not well comprehended. The current study examined haematological, biochemical, and antioxidant parameters, along with immunohistochemical and histological indications in tilapia (Oreochromis niloticus) after being exposed to tadalafil, polyethylene microplastics (PE-MPs), and their mixtures for 15 days. The fish were distributed into 1st group control group (The fish was maintained in untreated water without any supplements); 2nd group exposed to 10 mg/L PE-MPs;3rd group exposed to 20 mg/l tadalafil (Cilais); 4th group exposed to 20 mg/l tadalafil (Cilais) + 10 mg/LPE-MPs (in triplicate). The levels of creatinine, uric acid, glucose, AST, ALT, and albumin in fish treated with tadalafil alone or in combination with PE-MPs were significantly higher than those in the control group. Fish exposed to PE-MPs, tadalafil, and tadalafil plus PE-MPs showed significantly lower levels of RBCs, Hb, Ht, neutrophils, and lymphocytes compared to the control group. Serum levels of total antioxidant capacity and reduced glutathione (GSH) were notably lowered in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations in comparison to the control group. Malondialdehyde (MDA) serum levels were notably elevated in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations compared to the control group. The most severe impact was observed in the tadalafil + PE-MPs combination group. Interleukin-6 (IL-6) levels were significantly increased in liver tissues following exposure to both tadalafil and microplastics compared to tissues exposed to only one substance or the control group. Changes in the gills, liver, and renal tissues were seen following exposure to PE-MPs, tadalafil, and tadalafil + PE-MPs combination in comparison to the control group of fish. Ultimately, the mixture of tadalafil and PE-MPs resulted in the most detrimental outcomes. Tadalafil and PE-MPs exhibited showed greater adverse effects, likely due to tadalafil being absorbed onto PE-MPs.

Abstract Fluorescence nanoscopy, also known as super-resolution microscopy, has transcended the conventional resolution barriers and enabled visualization of biological samples at nanometric resolutions. A series of super-resolution techniques have been developed and applied to investigate the molecular distribution, organization, and interactions in blood cells, as well as the underlying mechanisms of blood-cell-associated diseases. In this review, we provide an overview of various fluorescence nanoscopy technologies, outlining their current development stage and the challenges they are facing in terms of functionality and practicality. We specifically explore how these innovations have propelled forward the analysis of thrombocytes (platelets), erythrocytes (red blood cells) and leukocytes (white blood cells), shedding light on the nanoscale arrangement of subcellular components and molecular interactions. We spotlight novel biomarkers uncovered by fluorescence nanoscopy for disease diagnosis, such as thrombocytopathies, malignancies, and infectious diseases. Furthermore, we discuss the technological hurdles and chart out prospective avenues for future research directions. This review aims to underscore the significant contributions of fluorescence nanoscopy to the field of blood cell analysis and disease diagnosis, poised to revolutionize our approach to exploring, understanding, and managing disease at the molecular level. Graphical Abstract

Abstract Background While tuberculosis (TB) remains a significant global health threat, data on mortality in critically ill TB patients and those with drug-resistant TB (DR-TB) is limited. This study explores hematological profiles of critically ill TB patients and those with DR-TB, investigating associations with in-hospital and short-term mortality. Methods A longitudinal study of 269 patients with confirmed TB evaluated baseline blood cell counts and indices from medical records. We calculated in-hospital mortality and short-term prognosis, followed by analysis to identify predictors of mortality using hematological parameters. Results One-third of TB patients were critically ill (35.32%) and required intensive care unit (ICU) admission, while 14.5% had DR-TB, more common in females and smokers. Critically ill patients were older and tended to be non-smokers. DR-TB patients exhibited elevated lymphocyte and monocyte counts but lower neutrophil count and blood indices. Critically ill DS-TB patients had lower hemoglobin (Hb) and platelet (PLT) but higher total leucocytes count (TLC) and mean platelet volume (MPV). In-hospital mortality rate was 29.37%, significantly higher in critically ill DS-TB patients (74.74%). In-hospital mortality was 14-fold higher in critically ill DS-TB patients, 11-fold higher in stable DR-TB patients, and 6-fold higher in patients with comorbidities. Decreased Hb, monocyte level, and neutrophil to lymphocyte ratio (NLR) were significantly associated with in-hospital mortality. Predictors of short-term mortality included critical illness and comorbidities. However, the effect of DR-TB on short-term mortality disappeared. Decreasing Hb and TLC, especially neutrophils were significantly linked to short-term mortality. The utility of Hb in discriminating in-hospital and short-term mortality was very good, with AUC values of 78% and 79%, respectively. Cutoff values of less than 10 mg/dL and 9.75 mg/dL showed sensitivity ranging from 71 to 80% and specificity ranging from 75 to 80%, respectively. Conclusion This study provides valuable insights into patients with DR-TB and DS-TB with critically illness. We observed elevated lymphocyte and monocyte counts in DR-TB patients, as well as significant alterations in blood indices in critically ill patients. Importantly, the in-hospital mortality was notably higher in critically ill DS-TB patients, highlighting the importance of early recognition and aggressive management in this subgroup. Specifically, certain blood parameters such as hemoglobin, monocytes, neutrophils, and the NLR were associated with an increased risk of both in-hospital and short-term mortality. Furthermore, our findings underscore the prognostic significance of hematological parameters, particularly in resource-limited settings.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future. [ABSTRACT FROM AUTHOR]

Reptile white blood cell (WBC) morphological features are strikingly variable across species. In the Argentine black and white tegu (Salvator merianae), red tegu (Salvator rufescens), and Savannah monitor (Varanus exanthematicus), previous reports described a WBC type with a single distinct, clear, linear- to ovoid- to crescent-shaped inclusion of presumptive monocytic origin. The objective of this study was to further investigate the origin of this unique WBC type with crescent-shaped inclusions. Blood samples from two Argentine black and white tegus, tegu 1, a 4-year-old female, and tegu 2, a 2-year-old presumed male, were submitted for routine hematological evaluation. Additional blood films were prepared and stained with these cytochemical stains: alkaline phosphatase (ALP; naphthol AS-MX phosphate substrate), alpha-naphthyl butyrate esterase, alphachloroacetate esterase, myeloperoxidase, Periodic acid-Schiff, and Sudan black B. Blood films from tegu 1 were also stained with a second ALP stain (5-bromo- 4-chloro-3-indoxyl-phosphate and nitroblue tetrazolium substrate), Luna, luxol fast blue, and toluidine blue. The blood from tegu 1 was cytocentrifuged to isolate and fix the buffy coat in glutaraldehyde 2.5% aqueous solution for transmission electron microscopy. Six morphologically distinct WBC types were identified from tegu 1, including heterophils, basophils, monocytes, azurophils, lymphocytes, and the unique WBC type, which were identified as eosinophils with inclusions. WBC types in tegu 2 were similar; however, eosinophils lacked a discernable inclusion. Proper WBC identification will be useful in obtaining accurate hemogram data for this species. [ABSTRACT FROM AUTHOR]

The joint impact of tadalafil (Cilais) as a pharmaceutical residue and microplastics on fish is not well comprehended. The current study examined haematological, biochemical, and antioxidant parameters, along with immunohistochemical and histological indications in tilapia (Oreochromis niloticus) after being exposed to tadalafil, polyethylene microplastics (PE-MPs), and their mixtures for 15 days. The fish were distributed into 1st group control group (The fish was maintained in untreated water without any supplements); 2nd group exposed to 10 mg/L PE-MPs;3rd group exposed to 20 mg/l tadalafil (Cilais); 4th group exposed to 20 mg/l tadalafil (Cilais) + 10 mg/LPE-MPs (in triplicate). The levels of creatinine, uric acid, glucose, AST, ALT, and albumin in fish treated with tadalafil alone or in combination with PE-MPs were significantly higher than those in the control group. Fish exposed to PE-MPs, tadalafil, and tadalafil plus PE-MPs showed significantly lower levels of RBCs, Hb, Ht, neutrophils, and lymphocytes compared to the control group. Serum levels of total antioxidant capacity and reduced glutathione (GSH) were notably lowered in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations in comparison to the control group. Malondialdehyde (MDA) serum levels were notably elevated in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations compared to the control group. The most severe impact was observed in the tadalafil + PE-MPs combination group. Interleukin-6 (IL-6) levels were significantly increased in liver tissues following exposure to both tadalafil and microplastics compared to tissues exposed to only one substance or the control group. Changes in the gills, liver, and renal tissues were seen following exposure to PE-MPs, tadalafil, and tadalafil + PE-MPs combination in comparison to the control group of fish. Ultimately, the mixture of tadalafil and PE-MPs resulted in the most detrimental outcomes. Tadalafil and PE-MPs exhibited showed greater adverse effects, likely due to tadalafil being absorbed onto PE-MPs. [ABSTRACT FROM AUTHOR]

Fluorescence nanoscopy, also known as super-resolution microscopy, has transcended the conventional resolution barriers and enabled visualization of biological samples at nanometric resolutions. A series of super-resolution techniques have been developed and applied to investigate the molecular distribution, organization, and interactions in blood cells, as well as the underlying mechanisms of blood-cell-associated diseases. In this review, we provide an overview of various fluorescence nanoscopy technologies, outlining their current development stage and the challenges they are facing in terms of functionality and practicality. We specifically explore how these innovations have propelled forward the analysis of thrombocytes (platelets), erythrocytes (red blood cells) and leukocytes (white blood cells), shedding light on the nanoscale arrangement of subcellular components and molecular interactions. We spotlight novel biomarkers uncovered by fluorescence nanoscopy for disease diagnosis, such as thrombocytopathies, malignancies, and infectious diseases. Furthermore, we discuss the technological hurdles and chart out prospective avenues for future research directions. This review aims to underscore the significant contributions of fluorescence nanoscopy to the field of blood cell analysis and disease diagnosis, poised to revolutionize our approach to exploring, understanding, and managing disease at the molecular level. [ABSTRACT FROM AUTHOR]

Background: Despite emerging evidence linking blood cell indices (BCIs) to sepsis mortality, the inconsistency of observational studies obscures the clarity of these associations. This study aims to clarify the causal influence of BCIs on 28-day mortality rates in sepsis patients. Methods: Utilizing univariable and multivariable Mendelian randomization (MR) analyses, we examined the impact of BCIs on sepsis mortality by analyzing data from extensive genome-wide association studies. The inverse-variance weighted (IVW) method was our primary analytic tool, complemented by several robustness checks to mitigate pleiotropy, including weighted median, mode-based estimates, MR-Egger regression, and MR-PRESSO. Subsequently, we conducted a retrospective study to further explore the correlation between platelet indices and 28-day mortality of sepsis using real-world data. Results: Our findings highlight a significant causal relationship between platelet distribution width (PDW) and 28-day mortality in sepsis, with the univariable Mendelian randomization approach yielding an odds ratio of 1.12 (95% CI, 1.06–1.26; P < 0.05). Multivariable analysis further substantiated PDW's robust association with mortality risk (OR 1.23; 95% CI, 1.03–1.48; P < 0.05). Conversely, our analysis did not uncover significant correlations between the genetic predispositions to other BCIs—including red blood cell count, erythrocyte distribution width, platelet count, mean platelet volume, white blood cell count, neutrophil count, neutrophil percentage, lymphocyte count, and lymphocyte percentage—and 28-day mortality in sepsis. Additionally, an inverse MR analysis did not establish a causal impact of 28-day mortality in sepsis on PDW (OR 1.00; 95% CI, 1.00—1.07; P = 0.29). Moreover, a similar result was observed in the retrospective study. Conclusions: The study underscores the independent causal role of PDW in predicting 28-day mortality in sepsis, suggesting its potential utility in early patient assessment, risk stratification, and tailoring of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Separating plasma from whole blood is an important sample processing technique required for fundamental biomedical research, medical diagnostics, and therapeutic applications. Traditional protocols for plasma isolation require multiple centrifugation steps or multiunit microfluidic processing to sequentially remove large red blood cells (RBCs) and white blood cells (WBCs), followed by the removal of small platelets. Here, we present an acoustofluidic platform capable of efficiently removing RBCs, WBCs, and platelets from whole blood in a single step. By leveraging differences in the acoustic impedances of fluids, our device generates significantly greater forces on suspended particles than conventional microfluidic approaches, enabling the removal of both large blood cells and smaller platelets in a single unit. As a result, undiluted human whole blood can be processed by our device to remove both blood cells and platelets (>90%) at low voltages (25 Vpp). The ability to successfully remove blood cells and platelets from plasma without altering the properties of the proteins and antibodies present creates numerous potential applications for our platform in biomedical research, as well as plasma-based diagnostics and therapeutics. Furthermore, the microfluidic nature of our device offers advantages such as portability, cost efficiency, and the ability to process small-volume samples. [ABSTRACT FROM AUTHOR]

Background: Investigating novel therapeutic strategies for colorectal cancer (CRC) is imperative. However, there is limited research on the use of drugs to target peripheral blood immune cells in this context. To address this gap, we performed a two-sample Mendelian randomization (MR) analysis to identify potential therapeutic targets for CRC. Methods: We applied two-sample MR to identify the causal relationship between peripheral blood immune cells and CRC. GWAS data were obtained from the IEU OPEN GWAS project. Based on the implications from the MR results, we conducted a comprehensive database search and genetic analysis to explore potential underlying mechanisms. We predicted miRNAs for each gene and employed extensive research for potential therapeutic applications. Results: We have identified causal associations between two peripheral immune cells and colorectal cancer. Activated & resting Treg %CD4 + cell was positively associated with the risks of CRC, while DN (CD4-CD8-) %leukocyte cell exhibited a protective role in tumor progression. NEK7 (NIMA related kinase 7) and LHX9 (LIM homeobox 9) expressed in Treg cells were positively associated with CRC risks and may play a vital role in carcinogenesis. Conclusions: This study identified causal relationship between peripheral immune cell and CRC. Treg and DN T cells were implicated to own promoting and inhibiting effects on CRC progression respectively. NEK7 and LHX9 in Treg cells were identified as potential biotarget for antitumor therapies. [ABSTRACT FROM AUTHOR]

The leaf‐cutter ant Atta sexdens is crucial in ecological balance and economic activities, due to its contribution to the aeration and accumulation of organic matter in the soil, but it may also be an agricultural pest when it defoliates plants for the fungus growth used as a food source. This leaf‐cutter ant exhibits a polymorphic worker caste system with distinct activities in the colony. These functions are performed by workers classified into subcastes, including gardeners, which are responsible for the fungus and brood care; cleaners (waste removers), which remove wastes; foragers, which collect and transport plant parts to the nest; and soldiers, which are responsible for colony defence and the support of foraging activities. In our previous work, we showed that A. sexdens has five types of circulating haemocytes in the haemolymph, which play a vital role in immune defence. Herein, we further investigated the population profile of circulating haemocytes in the haemolymph of different worker subcastes of A. sexdens using flow cytometry. Each subcaste exhibited a single population of haemocytes in the haemolymph. However, a detailed 3D dispersion analysis uncovered five distinct haemocyte subpopulations, two of which presented higher quantities. The soldier displayed haemocytes with high fluorescence intensity, compared with the gardener, waste remover, and forager, along with increased complexity, compared with the gardener subcaste. These results suggest that these cells may be granulocytes and plasmatocytes, which are known for their role in insect immune defence. [ABSTRACT FROM AUTHOR]

Adult neurogenesis, which takes place in both vertebrate and invertebrate species, is the process by which new neurons are born and integrated into existing functional neural circuits, long after embryonic development. Most studies in mammals suggest that self-renewing stem cells are the source of the new neurons, although the extent of self-renewal is a matter of debate. In contrast, research in the crayfish Procambarus clarkii has demonstrated that the neural progenitors producing adult-born neurons are capable of both self-renewing and consuming (non-self-renewing) divisions. However, self-renewing divisions are relatively rare, and therefore the production of adult-born neurons depends heavily on progenitors that are not replenishing themselves. Because the small pool of neural progenitors in the neurogenic niche is never exhausted throughout the long lives of these animals, we hypothesized that there must also be an extrinsic source of these cells. It was subsequently demonstrated that the neural progenitors originate in hemocytes (blood cells) produced by the immune system that travel in the circulation before ultimately integrating into niches where the neural lineage begins. The current study examines the developmental lineage of the three hemocyte types — hyaline (HC), semigranular (SGC) and granular (GC) cells — with the goal of understanding the origins of the progenitor cells that produce adult-born neurons. Longstanding qualitative metrics for hemocyte classification were validated quantitatively. Then, in a longitudinal study, proliferation markers were used to label the hemocytes in vivo, followed by sampling the circulating hemocyte population over the course of two months. Hemolymph samples were taken at intervals to track the frequencies of the different hemocyte types. These data reveal sequential peaks in the relative frequencies of HCs, SGCs and GCs, which were identified using qualitative and quantitative measures. These findings suggest that the three hemocyte types comprise a single cellular lineage that occurs in the circulation, with each type as a sequential progressive stage in hemocyte maturation beginning with HCs and ending with GCs. When combined with previously published data, this timeline provides additional evidence that HCs serve as the primary neural progenitor during adult neurogenesis in P. clarkii. [ABSTRACT FROM AUTHOR]

Background: There is a significant demand for intermediate-scale bioreactors in academic and industrial institutions to produce cells for various applications in drug screening and/or cell therapy. However, the application of these bioreactors in cultivating hiPSC-derived immune cells and other blood cells is noticeably lacking. To address this gap, we have developed a xeno-free and chemically defined intermediate-scale bioreactor platform, which allows for the generation of standardized human iPSC-derived hematopoietic organoids and subsequent continuous production of macrophages (iPSC-Mac). Methods: We describe a novel method for intermediate-scale immune cell manufacturing, specifically the continuous production of functionally and phenotypically relevant macrophages that are harvested on weekly basis for multiple weeks. Results: The continuous production of standardized human iPSC-derived macrophages (iPSC-Mac) from 3D hematopoietic organoids also termed hemanoids, is demonstrated. The hemanoids exhibit successive stage-specific embryonic development, recapitulating embryonic hematopoiesis. iPSC-Mac were efficiently and continuously produced from three different iPSC lines and exhibited a consistent and reproducible phenotype, as well as classical functionality and the ability to adapt towards pro- and anti-inflammatory activation stages. Single-cell transcriptomic analysis revealed high macrophage purity. Additionally, we show the ability to use the produced iPSC-Mac as a model for testing immunomodulatory drugs, exemplified by dexamethasone. Conclusions: The novel method demonstrates an easy-to-use intermediate-scale bioreactor platform that produces prime macrophages from human iPSCs. These macrophages are functionally active and require no downstream maturation steps, rendering them highly desirable for both therapeutic and non-therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: This study aimed to validate alterations in the gene expression of DNA methylation-related enzymes and global methylation in the peripheral blood mononuclear cell (PBMC) and synovial tissues of animal hip osteoarthritis (OA) models. Methods: Animals were assigned to the control (no treatment), sham (25 µL of sterile saline), and OA (25 µL of sterile saline and 2 mg of monoiodoacetate) groups. Microcomputed tomography scan, histopathological assessment and pain threshold measurement were performed after induction. The mRNA expression of the DNA methylation machinery genes and global DNA methylation in the PBMC and hip synovial tissue were evaluated. Results: The OA group presented with hip joint OA histopathologically and radiologically and decreased pain threshold. The mRNA expression of DNA methyltransferase (Dnmt 3a), ten–eleven translocation (Tet) 1 and Tet 3 in the synovial tissue of the OA group was significantly upregulated. Global DNA methylation in the synovial tissue of the OA group was significantly higher than that of the control and sham groups. Conclusions: The intra-articular administration of monoiodoacetate induced hip joint OA and decreased pain threshold. The DNA methylation machinery in the synovial tissues of hip OA was altered. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of vitiligo remains elusive. Emerging evidence suggests that vitiligo is an immune-mediated disorder, in which a plethora of immune cells play pivotal roles. However, the association between circulating immune cells and vitiligo continues to be enigmatic. Materials and methods: We extracted single nucleotide polymorphisms (SNPs) associated with immune circulating cells at a genome-wide significance level from the BLOOD CELL CONSORTIUM’s genome-wide association study (GWAS) dataset. Summary data for 385,801 cases of vitiligo were obtained from a largescale Finnish genome-wide association study (ncases=292, ncontrols=385,509). The inverse variance weighted (IVW) method was employed as the primary analytical approach for Mendelian randomization (MR) analysis. Additionally, heterogeneity was assessed using Cochran’s Q value, and horizontal pleiotropy was evaluated using MR-Egger Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses. Results: The risk of vitiligo was found to increase with the elevation of 4 circulating immune cells, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs): basophils (OR=1.81; 95% CI: 1.01–3.24, p=0.0450), monocytes (OR=1.67; 95% CI: 1.23–2.26, p=0.0009), eosinophils (OR=1.78; 95% CI: 1.22–2.59, p=0.0028), and neutrophils (OR=1.65; 95% CI: 1.08–2.54, p=0.0208). After removing outliers, the sensitivity analysis of the above indicators did not show heterogeneity and pleiotropy. Conclusion: Our findings illuminate the association between circulating immune cells and vitiligo, offering insights that could guide clinical practices in the treatment of vitiligo. [ABSTRACT FROM AUTHOR]

The association between leukemic stem cells (LSCs) and leukemia development has been widely established in the context of genetic alterations, epigenetic pathways, and signaling pathway regulation. Hematopoietic stem cells are at the top of the bone marrow hierarchy and can self-renew and progressively generate blood and immune cells. The microenvironment, niche cells, and complex signaling pathways that regulate them acquire genetic mutations and epigenetic alterations due to aging, a chronic inflammatory environment, stress, and cancer, resulting in hematopoietic stem cell dysregulation and the production of abnormal blood and immune cells, leading to hematological malignancies and blood cancer. Cells that acquire these mutations grow at a faster rate than other cells and induce clone expansion. Excessive growth leads to the development of blood cancers. Standard therapy targets blast cells, which proliferate rapidly; however, LSCs that can induce disease recurrence remain after treatment, leading to recurrence and poor prognosis. To overcome these limitations, researchers have focused on the characteristics and signaling systems of LSCs and therapies that target them to block LSCs. This review aims to provide a comprehensive understanding of the types of hematopoietic malignancies, the characteristics of leukemic stem cells that cause them, the mechanisms by which these cells acquire chemotherapy resistance, and the therapies targeting these mechanisms. [ABSTRACT FROM AUTHOR]

Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer mitochondria to myeloid cells. Impairment of the transfer of mitochondria by deleting MIRO1 in osteolineage cells leads to increased myeloid cell commitment toward osteoclastic lineage cells and promotes bone resorption. In detail, impaired mitochondrial transfer from osteolineage cells alters glutathione metabolism and protects osteoclastic lineage cells from ferroptosis, thus promoting osteoclast activities. Furthermore, mitochondrial transfer from osteolineage cells to myeloid cells is involved in the regulation of glucocorticoid-induced osteoporosis, and glutathione depletion alleviates the progression of glucocorticoid-induced osteoporosis. These findings reveal an unappreciated mechanism underlying the interaction between osteolineage cells and myeloid cells to regulate skeletal metabolic homeostasis and provide insights into glucocorticoid-induced osteoporosis progression. Bone and blood lineage cells communicate with each other to maintain skeletal homeostasis. Here, the authors show that MIRO1-mediated mitochondrial transfer from osteolineage to myeloid lineage cells regulates bone resorption by altering glutathione metabolism. [ABSTRACT FROM AUTHOR]

Bone resorption is driven through osteoclast differentiation by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-Β ligand (RANKL). We noted that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 are downregulated at the expression level during osteoclast differentiation of the murine monocytic cell line RAW264.7 in response to RANKL. Both proteinases are well known to shed a variety of single-pass transmembrane molecules from the cell surface. We further showed that inhibitors of ADAM10 or ADAM17 promote osteoclastic differentiation and furthermore enhance the surface expression of receptors for RANKL and M-CSF on RAW264.7 cells. Using murine bone marrow-derived monocytic cells (BMDMCs), we demonstrated that a genetic deficiency of ADAM17 or its required regulator iRhom2 leads to increased osteoclast development in response to M-CSF and RANKL stimulation. Moreover, ADAM17-deficient osteoclast precursor cells express increased levels of the receptors for RANKL and M-CSF. Thus, ADAM17 negatively regulates osteoclast differentiation, most likely through shedding of these receptors. To assess the time-dependent contribution of ADAM10, we blocked this proteinase by adding a specific inhibitor on day 0 of BMDMC stimulation with M-CSF or on day 7 of subsequent stimulation with RANKL. Only ADAM10 inhibition beginning on day 7 increased the size of developing osteoclasts indicating that ADAM10 suppresses osteoclast differentiation at a later stage. Finally, we could confirm our findings in human peripheral blood mononuclear cells (PBMCs). Thus, downregulation of either ADAM10 or ADAM17 during osteoclast differentiation may represent a novel regulatory mechanism to enhance their differentiation process. Enhanced bone resorption is a critical issue in osteoporosis and is driven through osteoclast differentiation by specific osteogenic mediators. The present study demonstrated that the metalloproteinases ADAM17 and ADAM10 critically suppress osteoclast development. This was observed for a murine cell line, for isolated murine bone marrow cells and for human blood cells by either preferential inhibition of the proteinases or by gene knockout. As a possible mechanism, we studied the surface expression of critical receptors for osteogenic mediators on developing osteoclasts. Our findings revealed that the suppressive effects of ADAM17 and ADAM10 on osteoclastogenesis can be explained in part by the proteolytic cleavage of surface receptors by ADAM10 and ADAM17, which reduces the sensitivity of these cells to osteogenic mediators. We also observed that osteoclast differentiation was associated with the downregulation of ADAM10 and ADAM17, which reduced their suppressive effects. We therefore propose that this downregulation serves as a feedback loop for enhancing osteoclast development. [ABSTRACT FROM AUTHOR]