Introduction: The identification of some prognostic markers in head and neck cancers (HNC) is necessary for the stratification of the therapeutic approach with benefits in increasing treatment response rates and limiting the toxic side effects of treatments. Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and pallets-to-lymphocyte ratio (PLR) are currently validated as cheap and accessible biomarkers in different types of solid tumors. The purpose of the study was to evaluate the possible biomarker value of NLR, PLR and MLR recorded pre-treatment (radiotherapy/chemotherapy) for prognostic purposes in HNC. Materials and methods: The study included 190 patients with HNC included in the oncology record in the oncology outpatient clinic of the Craiova County Emergency Hospital starting from January 2002 and deceased until December 2022. Among them, 40 patients treated multimodally in the Clinic were included in the study of Oncology of the Craiova County Emergency Hospital for which the pre-treatment value (chemotherapy/radiotherapy) of NLR, PLR and MLR could be calculated. Overall survival (OS) values were correlated with NLR, PLR and MLR. Results: Median values for NLR, PLR and MLR were 6.15 (1.24-69), 200.79 (61.3- 1775.0) and 0.53 (0.12-5.5) respectively. In the study, the mean values for NLR, PLR and MLR of 2.88, 142.97 and 0.36 respectively were obtained. Median OS in the study group was 11 months (1-120). Although a negative Pearson`s correlation, the relationship between your variables was only weak, values R =.07, p=.67; R=.02, p=.31 and R=07, p=.62 being related with NLR, PLR and MLR respectively correlation with overall survival (OS). The median values of NLR, PLR and MLR were calculated (1.53, 90.32 and 0.18 respectively) for HNC cases with pre-treatment values of NLR <2 and for HNC cases with NLR values ≥6 (23.5, 232.78 and 0.79 respectively). Median OS for cases with NLR<2 and NLR≥6 were 17.4 and 13 months, respectively. Conclusions: The negative correlations of NLR, PLR and MLR with OS reported in the study are in accordance with the data reported in the literature for locally advanced recurrent and metastatic HNSCC cases. The comparative analysis of the data in the group with NLR<2 and NLR≥6 highlights an advantage of 4.4 months in median OS in favor of the group with low values of NLR. Being cheap and accessible, these markers could change the therapeutic approach even in centers with limited resources. The role of borderline NLR values as a prognostic factor in HNSCC must also be defined. PLR and MLR are less evaluated as biomarkers but the study demonstrates their potential to be used as prognostic biomarkers, it remains to be clarified if their inclusion in multivariable models along with NLR would bring a benefit

With covid infection having a periodic occurrence and each wave affecting millions of people, there is an urgent need for healthcare providers to develop readily available biological markers to predict the severity and mortality of COVID-19 infection at an early stage of the disease to predict the most optimal management. The Neutrophil – lymphocyte Ratio (NLR) and Platelet-lymphocyte ratio (PLR), are novel inflammatory markers suggested to predict the severity of illness in COVID -19 patients. We evaluated a retrospective cohort of 224 patients with covid 19 illnesses from August 2020 to October 2020. We categorized the patients into 'mild' and 'moderate to severe as per the severity of their illnesses. The optimal cut-off values of the continuous NLR, PLR, and Age were calculated by applying the receiver operating characteristic (ROC) curve analysis. Sensitivity, specificity, and likelihood ratios were calculated from ROC analysis. The results showed that Age, Hb, and NLR are significant predictors of the severity of illness. So we quantified the predictive contribution of those variables by its Z- score and showed that NLR is the strongest predictor followed by Age.ROC curve analysis revealed NLR to be an excellent predictor of disease severity (sensitivity 88.30% and specificity 82.60%) at a cut-off of > 4.24. A cut-off of 165.63 was obtained for PLR, which showed good predictive value for the severity of illness. A NLR > 6 was used as a predictor for mortality due to covid illness with good sensitivity and specificity. Conclusion: NLR and PLR can be used as prognostic markers to identify the severity of covid illness and the probability of mortality in the future in low-resource settings. Given its low cost, easily available, accessible, and reproducible data, it can be used as a useful marker to assist the physician in early referral and treatment of covid 19 infected patients.

The study comprehensively evaluated the prognostic roles of PLR, NLR, MLR, BLR, and ELR in patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD). 619 patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics containing laboratory findings of the AECOPD patients and the blood cell counts (CBCs) of the healthy volunteers were collected. Compared with the healthy volunteers, PLR, NLR, and MLR were elevated in COPD patients in stable condition, and were further ele-vated during exacerbation. ELR showed the opposite trend. PLR, NLR, and MLR were all posi-tively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more serious airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while Elevated ELR was associated with decreased in-hospital mortality in AECOPD. A nomogram was construct to predict in-hospital mortality in AECOPD. The nomo-gram had a C-index of 0.850 (95% CI: 0.799 – 0.901) with good predictive value and clinical ap-plicability. In summary, PLR, NLR, MLR, and ELR served as predictors for clinical outcomes in patients with AECOPD.

Background: Psoriasis is a chronic immune-mediated skin disease in which systemic inflammation plays an important role in the pathogenesis. In recent years, neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-monocyte ratio (NMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been shown to be important indicators of inflammation. In this study, our aim is to investigate NLR, NMR, PLR, and SII levels in psoriasis patients treated with biologic agents. Method: Clinical and biochemical data of 209 patients who received systemic therapy for psoriasis were obtained by retrospectively reviewing their medical records. NLR, NMR, PLR, and SII values were calculated from the hemogram values of the patients. Results: In the third month of follow-up, the mean CRP, NLR, NMR, PLR, and SII values were significantly decreased compared to the baseline values. SII values showed strong positive correlations with NLR, NMR and PLR. Adalimumab, etanercept, and infliximab, which are TNF-α blockers, were observed to be more effective on PLR and NLR and especially NMR. Conclusion: NLR, NMR, PLR, and SII, which are data obtained from routine blood tests, can be used in the monitoring of treatment of psoriasis, especially with TNF- α blockers.

: Inflammation may mediate the association of mitral valve prolapse (MVP) with ventricular scarring and arrhythmia. The purpose of this study is to investigate the association of neutrophil- and platelet-to-lymphocyte ratios (NLR, PLR) with ventricular arrhythmia in MVP. Clinical and demographic data were extracted from electronic medical records for all patients aged 18-90 years with MVP on echocardiography between 2016-19 at our institution. We studied 65 patients who had a differential blood count within six months prior to ambulatory ECG (A- ECG) (medi-an age [IQR] 70 [61-77] years; 62% female; 12% African American). Patients with surgery or in-fection within six months prior to CBC were excluded. Complex or frequent ventricular ectopy (cfVE) was defined as the presence of two or more premature ventricular contractions (PVCs) on a 10-second ECG tracing or greater than 1% PVC burden or NSVT on ambulatory ECG monitoring. Logistic and bivariate regression was used to analyze clinical, electrocardiographic and echo-cardiographic factors associated with NLR and PLR. Factors associated with higher NLR were congestive heart failure (p=0.005), male sex (p=0.01), age (p=0.003), and bileaflet MVP (p=0.04). NLR was associated with higher absolute PVC burden (rs=0.28, p=0.03) and cfVE (median NLR [IQR] 3.0 [1.6 – 6.3]) with cfVE versus (2.4 [1.4-3.4], p=0.04) without cfVE. An NLR of 5.6 yielded 50% sensitivity and 90% specificity for PVC burden >1% (AUC 0.69). No significant association was found between PLR and PVC burden or cfVE. NLR is associated with PVC burden and com-plex ventricular ectopy in MVP, suggesting that inflammation is a significant factor in the patho-genesis of ventricular arrhythmia in this condition.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocytes count as lymphocytes and neutrophils. The neutrophil to lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. Clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups in regard to their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). Comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then Cox-regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p<0.0001) and with vital forced capacity (p=0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients’ survival.

Acoustic Radiation Forced Impulse (ARFI) is an ultrasound integrated method, measuring stiff-ness by point shear wave elastography. To evaluate the diagnostic performance of ARFI of the liver and of the spleen, combined with spleen dimension and platelet count, in predicting clinical events in cirrhosis, a prospective and cross-sectional study was conducted between February 2017 and February 2021. The following ratio scores with ARFI measurements were performed: ALSDP (ARFI Liver-Spleen Diameter-to-Platelets ratio score), ASSDP (ARFI Spleen-Spleen Diam-eter-to-Platelets ratio score), ASSAP (ARFI Spleen-Spleen Area-to-Platelets ratio score), ALSAP (ARFI Liver-Spleen Area-to-Platelets ratio score). In 100 enrolled subjects, spleen ARFI, ASSDP, ASSAP, were significantly associated with high-risk oesophageal varices (HRVs) in the prospec-tive short- and long-term follow-up and in the cross-sectional study (p 0.7). ARFI-ratio scores can predict, in cirrhotic patients, the risk of developing HVRs in short and long-term period.

Background: CD169 has been found overexpressed in the blood of COVID-19 patients and identified as a biomarker in the early disease. We have analysed CD169 in blood cells of COVID-19 patients to assess its role as predictive marker of the disease. Methods : The ratio of the CD169 Median median Fluorescence fluorescence Intensity intensity of CD169 between monocytes and lymphocytes (CD169 RMFI ) was analysed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HD ) and correlated with immunophenotyping, inflammatory markers, cytokines mRNA expression, pulmonary involvement and disease progression. Results: CD169 RMFI increased in COV but not in HD. CD169 RMFI correlated with T-cell differentiation and exhaustion markers as well as with B cells maturation and differentiation. In vitro stimulation of PBMCs of HD with SARS-CoV-2 Spike spike protein induced CD169 RMFI together with IL-6 and IL-10 gene expression. Likewise, CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients which that had not received any treatment at sampling. Notably, in untreated patients, CD169 RMFI reflected the respiratory outcome during hospitalization. Conclusion : Considering the immunological role of CD169 and its involvement during the infection and the progression of COVID-19, it could be considered as an early biomarker to evaluate disease progression and clinical outcome.

Background: Cutaneous Melanoma (SKCM) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of SKCM (n=328) was utilized. The immune microenvironment was characterized using CIBERSORTX to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Samples were separated into those obtained from the primary tumor site and regional skin or soft tissue (locoregional), or distant metastasis and regional lymph node (metastatic). Analysis of overall survival (OS) was performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by lymphocyte:monocyte (L:M) ratio, monocyte-enrichment, and M0-macrophage-enrichment (L:MLow, MonocyteHigh, M0High; L:MLow, MonocyteMid, M0Low; L:MMid, MonocyteLow, M0Low; L:MHigh, MonocyteLow, M0Low). The L:MLow, MonocyteHigh, M0High cluster demonstrated significantly worse OS than clusters 2-4 in the locoregional group (HR 2.804, 95% CI 1.262–6.234, p=0.0114). Membership in the L:MLow, MonocyteHigh, M0High cluster was an independently poor prognostic factor for survival (HR 3.03, 95% CI 1.12–8.20, p=0.029). The L:MLow, MonocyteHigh, M0High cluster correlated with higher rates of metastasis and decreased predicted response to immune checkpoint blockade compared to the other clusters as determined by the Tumor Immune Dysfunction and Exclusion tool (TIDE). Conclusion: Distinct tumor immune clusters with a M0-macrophage-enriched, L:M ratio low phenotype in the primary melanoma tumor site independently characterize an aggressive phenotype that may differentially respond to treatment.

Metabolic-associated fatty liver disease (MASLD) is not only associated with traditional cardiovascular risk factors such as T2DM and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulation cascade, decreased fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to have potential clinical implication for the prevention of HCC patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MAFLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

Neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR 6.97, 95% CI 1.65-10.55, p= 0.002) and OS (HR 7.79, 95% CI 1.25-15.07, p= 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67≥ 14% were also associated with worse DFS (p= 0.016, p= 0.002, and p= 0.001, respectively). In multivariate analysis, luminal B subtype, post-treatment Ki67≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

C-reactive protein to lymphocyte ratio (CLR) has been shown to be associated with diseases characterized by chronic, low-grade inflammation. Since type 2 diabetes (T2DM) is also associated with inflammation, we aimed to study the association between CLR and T2DM. Patients with T2DM who presented to internal medicine outpatient clinics of our institution were divided into 2 groups according to their glycosylated hemoglobin (HbA1c) levels as well-controlled (HbA1c&lt;7%) and poorly controlled (HbA1c≥7%) T2DM groups. Subjects assigned as healthy in routine check-up were included as control group. CLR values of the well and poorly controlled diabetics and control cases were compared. CLR of T2DM group (3.51 (0.03-21.78)) was significantly higher than that of the controls (0.65 (0.02-2.92)) (p&lt;0.001). CLR was found to have a sensitivity of 63.2% and a specificity of 97.3% in predicting T2DM. The CLR value of patients with poor diabetic control was 4.76 (0.06-21.78), while the CLR value of patients with well controlled disease was 2.53 (0.03-12.07) (p&lt;0.001). The sensitivity and specificity of the CLR in demonstrating poor diabetic control was 41.2% and the 86.1%, respectively. In conclusion, elevated CLR in T2DM patients and even more increased levels in poorly controlled diabetics suggest that CLR could be a useful additional diagnostic tool in treatment follow-up of the T2DM population.

Abstract: Systemic inflammatory response syndrome (SIRS) is a clinical diagnosis based on abnormalities in patients' vital signs and white blood cell count. Neutrophil-lymphocyte ratio (NLR) is used as an easily accessible parameter to assess the patient's inflammatory status and stress. There are some studies showing that NLR affected by the inflammatory response is a criterion to support the diagnosis of SIRS. In this study, it was aimed to compare the interrelation between SIRS (+) and SIRS (-) groups in patients with high positive feline coronavirus (FCoV) in the light of NLR. Based on the anamneses, physical examination findings, laboratory findings, enzyme immunoassay antibody test kit titer were included in the sick groups. These patients were further categorized based on the presence of SIRS symptoms, vital signs and laboratory findings. The NLR as diagnostic marker demonstrated to differ between high antibody titer FCoV positive and healthy cats. However the diagnostic significance of NLR remains questionable between the high antibody titer FCoV positive cats with SIRS (+) and SIRS (-). As a result of our study NLR can be used as a blood parameter like albumin/globulin ratio and elevated total bilirubin in cats with high FCoV antibody titer and high probability of developing FIP.

Ustekinumab, a new anti-interleukin-12/23 antibody, is an effective treatment for ulcerative colitis; however, data regarding predictive factors of its efficacy are limited. This study aimed to identify biomarkers that can predict the long-term outcome of ustekinumab treatment. We retrospectively reviewed the records of patients with active ulcerative colitis treated with ustekinumab at our hospital from June 2020 to January 2023. We divided patients into non-remission and remission groups, and examined whether baseline biomarkers, including C-reactive protein-to-lymphocyte ratio, and early treatment response could predict clinical remission at week 48 of ustekinumab treatment. Of the 33 patients included in the study, 21 (63.6%) were in clinical remission at week 48 of ustekinumab treatment. The baseline C-reactive protein-to-lymphocyte ratio value was identified as an independent prognostic factor for clinical remission at week 48 (odds ratio: 10, 95% confidence interval: 1.6–62.4, p=0.014), with the cutoff value of 3.353 showing excellent prognostic performance (sensitivity: 71.4%, specificity: 83.3%). Furthermore, the clinical response at week 4 (p=0.009) and that at week 8 (p=0.005) were significantly associated with clinical remission at week 48. The baseline C-reactive protein-to-lymphocyte ratio value and early treatment response are useful biomarkers to predict the long-term efficacy of ustekinumab treatment.

Emerging autologous cellular therapies that utilize platelet-rich plasma (PRP) applications have the potential to play adjunctive roles in a variety of regenerative medicine treatment plans. There is a global unmet need for tissue repair strategies to treat musculoskeletal (MSK) and spinal disorders, osteoarthritis (OA), and patients with chronic complex and recalcitrant wounds. PRP therapy is based on the fact that platelet growth factors (PGFs) support the three phases of wound healing and repair cascade (inflammation, proliferation, remodeling). Many different PRP formulations have been evaluated, originating from human, in vitro, and animal studies. However, recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, progress has been made in understanding PRP technology and the concepts for bioformulation, and new research directives and new indications have been suggested. In this review, we will discuss recent developments regarding PRP preparation and composition regarding platelet dosing, leukocyte activities concerning innate and adaptive immunomodulation, serotonin (5-HT) effects and pain killing. Furthermore, we discuss PRP mechanisms related to inflammation and angiogenesis in tissue repair and regenerative processes. Lastly, we will review the effect of certain drugs on PRP activity, and the combination of PRP and rehabilitation protocols.

To facilitate the computation of the uniaxial compressive strength value of the cemented paste backfill under the condition of high sand-cement ratio, and to analyze the size effect of the cemented paste backfill with high sand-cement ratio under varied aspect ratios, the cemented paste backfill specimens with sand-cement ratios of 8:1-24:1 and aspect ratios of 0.5, 1, and 2 were prepared. Through response surface experiments and finite element analysis, the influence of three aspect ratios on the cemented paste backfill strength was explored, and the failure characteristics and size effect mechanisms of cemented paste backfill with various aspect ratios were analyzed. The model of strength conversion between cemented paste backfill with different aspect ratios was established. The results show that the compressive strength of the cemented paste backfill decreases with the increase of the aspect ratio under the same mass concentration and sand-cement ratio. When the aspect ratio is 0.5 and 1, the splitting failure is the main factor; when the aspect ratio is 2, the shearing failure is the main factor. The three-dimensional stress caused by the end effect of the cemented paste backfill is the main reason for the high strength when the aspect ratio is 0.5. Due to the one-dimensional stress zone generated in the middle of the cemented paste backfill with an aspect ratio of 2 in the laboratory, its strength value is closer to the actual uniaxial compressive strength value of the cemented paste backfill. The strength values of the cemented paste backfill with aspect ratios of 0.5 and 1 were higher than the actual uniaxial compressive strength values in the laboratory. The rationality of the theoretical analysis was verified by the ABAQUS analysis results. According to the experimental results, a strength conversion model between different aspect ratios is established, which can provide a reference for the design of the uniaxial compressive strength of the cemented paste backfill.

Background: In recent years, whole blood parameters and derivatives have been used as prognostic criteria in the course of the disease in various diseases. The prognostic nutritional index (PNI), the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR) have been adapted as an indicator of inflammation and have been widely studied to define the severity of inflammation in some diseases. The aim of this study was to evaluate the relationship between parameters such as NLR, SII, PNI, controlling nutritional status (CONUT) score, nutritional risk index (NRI) and with immunonutrition status and disease activity in patients with ischemic stroke of small vessel, large vessel and other etiologies. Methods: We retrospectively evaluated the records of 1454 consecutive ischemic stroke patients hospitalized in the emergency department of Gaziosmanpasa Education and Research Hospital from 2019 to 2023. Results: Of the 1350 SVO patients included in the study, 58.8% had small vessel, 29.3% had large vessel and 11.9% had other etiologies. There was a significant difference between the 3 etiology groups for PNI and CONUT. The median PNI was 47.03 (41.33-52.85) in the other etiology group, 35.29 (33.69-37.25) in the small vessel group, and 34.11 (30.23-36.87) in the large vessel group. The CONUT median was 5(5-6) in the small vessel group, 5(4-6) in the large vessel group and 4(4-4) in the other etiology group. In addition, CONUT and PNI were also found to be independent risk factors for death. A negative significant correlation was observed between PNI and NLR (r:-0.692), SII (r:-0.591), CONUT (r:-0.685). Significant correlations were observed between CONUT and NLR (r:0.402), SII (r:0.312). Conclusion: PNI and SII were significantly associated with disease activity. PNI, CONUT and NRI as a more accurate prognostic indicator of nutritional status in patients with ischemic stroke of small vessel, large vessel and other etiologies. NLR and SII may be important predictive markers in the course and prognosis of stroke.

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0-30 minutes) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA 3 regulated store, given the observation of increased Ca2+ release inducible by low dose tBHQ. Intriguingly, longer-term (&gt;12 hours) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools, yet decreased Ca2+ release responses from tBHQ-sensitive SERCA 3 pool. Our results reveal differential effects of CDN1163 on Ca2+ stores regulated by distinct SERCA isoforms, prompting the need for careful interpretation of the compound’s effects, particularly in cells expressing multiple SERCA isoforms.

In this study, the impact of the addition of high-aspect-ratio nano-ettringite to photocurable epoxy acrylate resin was explored, with a specific focus on the changes observed in viscosity, shrinkage, tensile strength, and elongation at the break of composites formed. Herein, the nano-ettringite samples were modified using KH-570. The 3 wt% or 6 wt% KH-570-modified and unmodified nano-ettringite were dispersed into the resin by ultrasonic treatment in conjunction with mechanical stirring. The grafting effects of nano-ettringite onto KH-570 were analyzed through scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric (TG) analysis, and Fourier transform infrared spectroscopy (FTIR). The results demonstrate that increased dosages of unmodified and modified nano-ettringite led to increased viscosity of the composite while reducing shrinkage. At the same dosage, the photocurable resin with modified nano-ettringite demonstrated a lower shrinkage and a higher tensile strength. Notably, when the amount of modified nano-ettringite was 3 wt%, the highest tensile strength of the composite was 64.61 MPa, presenting a 72.57% increase compared to the blank sample. Furthermore, the incorporation of modified nano-ettringite as a filler provides a new perspective for improving the performance of photocurable epoxy acrylate resin composites.

The aim of this study was to compare the effect of using L-PRF in patients undergoing impacted lower third molar surgery with either primary or secondary closure techniques. Methods: This prospective, randomised, double-blind, split-mouth clinical trial was conducted in patients with bilateral lower impacted third molars of similar position. Primary closure was performed in group 1 and secondary closure in group 2. Group 1 closure technique was applied to one side of the patients and group 2 closure technique was applied to the other side at different times. Nine pa-tients were excluded from the study due to alveolitis and failure to attend regular control visits out of the 45 patients evaluated. Results: Of the 36 patients included in the study, 23 were female and 13 were male and the mean age was 22.42±3.36 years. The secondary closure group had lower VAS scores at hour 6 (p

Extracellular vesicles (EV) are a very heterogeneous group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular communication, both locally and systemically, since they induce signals and transfer their contents (proteins, lipids, RNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. How-ever, cell surface receptor-induced EV release is limited to cells from the immune system, includ-ing T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptor for antigen and several bioactive molecules, including proapoptotic proteins. These EV are thus specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we discuss the generation of EV by T lymphocytes and some potential therapeutic approaches of these EV.

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacks both GCN5 and PCAF in B cells. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We conclude that both GCN5 and PCAF are required for B cell development in vivo.

The first published description of intraovarian platelet-rich plasma (PRP) appeared in mid-2016, when a new experimental technique was successfully used in adult human ovaries to correct the reduced fertility potential accompanying advanced maternal age. Considering the potential therapeutic scope of intraovarian activated PRP and/or condensed platelet cytokines would likely cover both menopause treatment and infertility, the mainstream response has ranged from skeptical disbelief to welcome astonishment. Indeed, reports of restored menses in menopause (as an alternative to conventional hormone replacement therapy) and healthy term livebirths for infertility patients (either with IVF or as unassisted conceptions) after intraovarian PRP injection continue to draw notice. Yet any proper criticism of ovarian PRP applications will be difficult to rebut given the heterogenous patient screening, varied sample preparations, wide differences in platelet incubation and activation protocols, surgical/anesthesia techniques, and delivery methods. Notwithstanding these features, no adverse events have been reported thus far and ovarian PRP appears well tolerated by patients. Here, early research guiding the transition of ‘ovarian rejuvenation’ from experimental to clinical is outlined. Likely mechanisms are presented to explain results observed in both veterinary and human ovarian PRP research. Current and future challenges for intraovarian cytokine treatment are also discussed.

Angiogenesis is new blood vessel formation from existing vessels and is a critical first step in tissue repair following chronic disturbances in healing and degenerative tissues. Chronic pathoanatomic tissues are characterized by a high number of inflammatory cells, overexpression of inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), the presence of mast cells, T cells, reactive oxygen species, and matrix metalloproteinases, and a decreased angiogenic capacity. Multiple studies have demonstrated that autologous orthobiological cellular preparations (e.g., platelet-rich plasma [PRP]) im-prove tissue repair and regenerate tissues. There are many PRP devices on the market. Unfortunately, they differ greatly in platelet numbers, cellular composition, and bioformulation. PRP is a platelet concentrate consisting of a high concentration of platelets with or without certain leukocytes, platelet-derived growth factors (PGFs), cytokines, molecules, and signaling cells. Several PRP products have immunomodulatory capacities that can influence resident cells in a diseased microenvironment, inducing tissue repair or re-generation. Generally, PRP is a blood-derived product, regardless of its platelet number and bioformulation, and the literature indicates both positive and negative patient treatment outcomes. Strangely, the literature does not designate specific PRP preparation qualifications that can potentially contribute to tissue re-pair. Moreover, the literature scarcely addresses the impact of platelets and leukocytes in PRP on (neo)angiogenesis other than a general one-size-fits-all statement that “PRP has angiogenic capabilities.” Here, we review the cellular composition of all PRP constituents, including leukocytes, and describe the importance of platelet dosing and bioformulation strategies in orthobiological applications to initiate angiogenic pathways that re-establish microvasculature networks, facilitating the supply of oxygen and nutrients to impaired tissues.

Severe COVID-19 is frequently associated with thromboembolic complications. Increased platelet activation and platelet-leukocyte aggregate formation can amplify thrombotic responses by inducing tissue factor (TF) expression on leukocytes. Here, we characterized TF-positive extracellular vesicles (EVs) and their cellular origin in 12 patients suffering from severe COVID-19 (time course, 134 samples overall) and 25 healthy controls. EVs exposing phosphatidylserine (PS) were characterized by flow cytometry. Their cellular origin was determined by staining with anti-CD41, anti-CD45, anti-CD235a, and anti-CD105 as platelet, leukocyte, red blood cell, and endothelial markers. We further investigated the association of EVs with TF, platelet factor 4 (PF4), C-reactive protein (CRP) and high mobility group box-1 protein (HMGB-1). COVID-19 patients showed higher levels of PS-exposing EVs compared to controls. The majority of these EVs originated from platelets. A higher amount of EVs in patient samples were associated with CRP, HMGB-1, PF4, and TF, as compared to EVs from healthy donors. In COVID-19 samples, 16.5% of all CD41+ EVs displayed the leukocyte marker CD45, and 55.5% of all EV aggregates (CD41+CD45+) co-expressed TF, which reflects the interaction of platelets and leukocytes in COVID-19 on an EV level.

Platelet P2Y₁₂ is an important ADP receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio-analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma we demonstrate that UTP inhibits P2Y₁₂ but not P2Y₁ receptors and antagonises 10 μM ADP-induced platelet aggregation in a concentration-dependent manner with an IC₅₀ value of ~250 μM. An 8-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC₅₀ of 30 μM. The 4-thio analogue (4S-UTP) with an IC₅₀ of 7.5 μM was 33-fold more effective. A 3-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y₁₂ receptors was verified by P2Y₁₂ receptor binding and cAMP assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y₁₂ receptor antagonists that may be useful for therapeutic intervention.

This study uses a mass-spring-damping system to simulate the repeated strain of liquefaction cyclic triaxial tests. The two results are compared in this paper to understand the feasibility of the mass-spring-damping system developed in this paper and the feasibility of future research on this related topic and development potential. The main factors affecting this mode's repeated strain are the spring coefficient k and the external force Q0. The spring coefficient has an inverse relationship but does not increase in multiples. The external force has a direct proportional relationship but does not increase the result- a non-multiple increase. When the pore water pressure of the liquefied cyclic triaxial test specimen rises, it will cause the specimen to liquefy, decreasing effective stress, shear modulus G, and damping ratio D, causing an increase in strain. The shear modulus and damping ratio are related to the spring coefficients k and c. Both are variables that change with time. This article takes an original thin-tube specimen at point A in the Yunlin area in Taiwan as a testing example. Through Mathematica software, it can be obtained that the mass m=1kg, the spring coefficient k=244e-0.1t kgf/cm, and the damping coefficient c=0.739e-0.257t kgf-s/cm and external force Q0=10.1sin2πt kg; Finally, this study selected the original thin-tube specimens from four locations in the Yunlin area, and simulated the repeated strain amount of the cyclic triaxial test specimens through a spring-damping system. The results show that the spring-damping system is feasible for simulated cyclic triaxial tests because the model is simple and the parameters are easy to understand and obtain, which also shows the extensibility of this model. Preliminary results of the research show that this model can further simulate the repeated strain obtained by cyclic triaxial tests without considering the increased trend in pore water pressure and the decrease in effective stress during cyclic loading.

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s^-1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s-1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modelling informed by biology can provide new pathphysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

The objective of this study is to investigate the effect of the premixed ethanol ratio based on the same total heating value in-cylinder on the equivalence ratio distributions and the injected fuel droplet behavior in the cylinder of the RCCI engine. The spray simulation was conducted by dividing two-part. First, the spray validation simulations progressed to find the spray-influenced factor of the test injector. Next, the engine simulations were performed with the spray-influenced factor obtained from spray validation simulations to investigate the effect of the premixed ethanol ratio based on the same total heating value in-cylinder on the injected fuel atomization and the equivalence ratio distributions. The introduced total heating value was fixed at 595J based on the lower heating value of diesel 14mg. The heating value of the premixed ethanol ratio varied from 0% to 40% based on the same total heating value in-cylinder in steps of 10%. It was revealed that when the premixed ethanol ratio based on the same total heating value in-cylinder was increased, the spray tip penetration value was reduced from the time after 4deg of diesel injection start because of the short injection duration by the small amount of diesel fuel. The SMD value was also more enormous up to 32.58% with increasing the premixed ethanol ratio because of the low kinetic energy of the injected fuel by the short injection duration and the slow evaporation of the injected fuel by the low cylinder temperature.

The concept of {\it quantum ratio} emerged in the recent efforts to understand how Newton's equations appear for the center of mass (CM) of an isolated macroscopic body at finite body-temperatures, as the first approximation to quantum-mechanical equations. It is defined as $Q\equiv R_q/L_0$, where the quantum fluctuation range $R_q$ is the spatial extension of the pure-state CM wave function, whereas $L_0$ stands for the body's linear size (the space support of the internal, bound-state wave function). The two cases $R_q /L_0 \lesssim 1$ or $R_q/ L_0 \gg 1$, roughly correspond to the body's CM behaving classically or quantum mechanically, respectively. In the present note we elaborate more on this concept, illustrating it in several examples. An important notion following from introduction of the quantum ratio is that the elementary particles (thus the electron and the photon) are quantum mechanical, even when the environment-induced decoherence turns them into a mixed state. Decoherence and classical state should not be identified. This simple observation, further illustrationed by the consideration of a few atomic or molecular processes, may have significant implications on the way quantum mechanics works in biological systems.

Achieving the thermal conductivity required for efficient heat management in semiconductors and other devices requires the integration of thermally conductive ceramic fillers at concentrations of 60 vol% or higher. However, the increased filler content often negatively affects the mechanical properties of the composite matrix, limiting its practical applicability. To address this issue, in this paper, we present a new strategy to reduce the required ceramic filler content: the use of a thermally conductive ceramic composite filler with carbon nanotubes (CNT) grown on aluminum nitride (AlN). We have combined catalyst coating technology with vacuum filtration to ensure that the catalyst is uniformly applied to micrometer-sized AlN particles, followed by efficient and uniform synthesis of CNTs using a water-assisted process in a vertical furnace. By carefully controlling the number of vacuum filtration cycles and the growth time of the CNTs, we demonstrate precise control over the number and length of the CNT layers, thereby adjusting the properties of the composite to the intended specifications. When AlN/CNT hybrid fillers are incorporated into silicone rubber, while maintaining the mechanical properties of rubber, the thermal diffusivity achieved at reduced filler levels exceeds that of composites using AlN-only or simultaneous AlN and CNTs formulations. This demonstrates the critical role of CNTs on AlN surfaces. Our study represents a significant advancement in the design of thermally conductive materials with potential implications for a wide range of applications.

Extracellular vesicles (EVs) present a great potential for the development of new treatments in the biomedical field. To be used as therapeutics, many different sources have been used for EVs obtention, while only few studies have addressed the use of platelet derived EVs (pEVs). In fact, pEVs have been shown to intervene in different healing responses, thus some studies have evaluated their regenerative capability in wound healing or hemorrhagic shock. Even more, pEVs have proven to induce cellular differentiation, enhancing musculoskeletal or neural regeneration. However, the obtention and characterization of pEVs is widely heterogeneous and differs from the recommendations of the International Society for Extracellular Vesicles. Therefore, in this review, we aim to present the main advances in the therapeutical use of pEVs in the regenerative medicine field while highlighting the isolation and characterization steps followed. The main goal of this review is to portray the studies performed in order to enhance the translation of the pEVs research into feasible therapeutical applications.

Aim: In the present work we have studied the role of platelets and microvesicles in patients with severe hemophilia A (HA) treated under the regimen of prophylaxis. We have analyzed whether the administration of coagulation factor FVIII modifies this hemorrhagic phenotype in a cohort of 16 patients with diagnosis of severe HA, who were on prophylactic treatment with recombinant FVIII. Methods: Blood tests were performed before (72h without FVIII, baseline sample) and after 15 minutes of FVIII infusion. As a control group, 15 healthy subjects were studied. Platelet aggregation was determined by closure time, optical aggregation, impedance aggregation and flow cytometry. We also studied the expression of the platelet activation markers P-selectin, CD63, platelet-tissue factor, formation of platelet-leukocyte aggregates and tissue factor exposure. The total number of platelet and endothelial microvesicles were also analyzed by flow cytometry, as well as platelet cytosolic Ca²⁺ mobilization. Results: We found no significant differences in platelet function in patients with severe HA in prophylactic treatment before and after FVIII infusion. After FVIII administration, patients presented fewer endothelial microvesicles, indicating that the treatment does not increase one of the possible thrombotic risk markers of these patients. The total amount of plasma microvesicles and the platelet microvesicles were decreased in patients with HA compared to the control group. Conclusions: Our results do not support any effect of FVIII on platelet function in patients with severe HA treated under the regime of prophylaxis.

On a bleak therapeutic landscape unchanged since the 1980’s, IVF with egg donation still stand as the lone medical answer to diminished reserve and premature ovarian insufficiency. Intraovarian platelet-rich plasma (PRP) crossed the horizon in 2016 as hopeful answer to these intertwined problems. The once remote mirage of platelet cytokine effects on gene regulation or telomere stabilization is now in sharper focus, and current work is clarifying how PRP corrects oxidative stress, rectifies tissue hypoxia, downregulates apoptosis, and enhances cellular metabolism. Not yet ready for routine use, this investigational treatment does offer one point of general agreement: How intraovarian PRP results should be classified—Patients are either responders or non-responders. From this, it is intriguing that no published PRP protocol has reported a supranormal ovarian rebound or hyperstimulation effect. This could be explained by baseline age-related ovarian conditions prevalent among poor responders, but since dysregulated or malignant transformations are also absent in other tissue contexts following autologous PRP treatment, the contribution of some platelet product which intrinsically delimits regenerative action cannot be discounted. Here we summarize results with recent experimental and clinical platelet research, framing those most likely to help advance reproductive endocrinology practice.

The golden ratio, also known as Phi (ϕ ≈ 1.618034), attracted the interest of mathematicians, artists, and intellectuals for many centuries, probably from when it was discovered in human anthropometry. Even in recent times, researchers found the presence of golden ratio in Renaissance paintings and aesthetic preferences. The reasons behind the fascination with the golden ratio remain unclear, but it has been suggested that stimuli containing this proportion are often perceived as beautiful. However, evidence is conflicting, and the literature struggles to establish the existence of individual preferences for golden ratio. To gain new insights into the nature of these preferences, one hundred participants completed an implicit association task, with either golden ratio or random stimuli presented with positive or negative words. Participants initially categorized the stimuli based on their assigned categories. Then, we assessed their explicit preferences by asking to rate the stimuli in terms of pleasantness and by completing a line bisection task and the Ultimate Game. The results revealed the typical effects observed in implicit association tasks, with improved response times and accuracy when golden ratio stimuli were associated with positive word categories. In contrast, explicit ratings yielded mixed results. We discuss our findings in relation to previous studies that have explored this issue, highlighting the ongoing debate surrounding preferences for the golden ratio.

Human Platelet lysate, a hemoderivative product rich in growth factors, holds significant promise in tissue engineering and regenerative medicine. However, its practical utility in liquid or gel form is hampered by challenges such as limited stability and handling difficulties. This study aimed to engineer dry and porous aerogels from platelet lysate hydrogel using an environmen-tally friendly supercritical CO2-based shaping process customized for tissue engineering appli-cations. The resulting aerogels demonstrated remarkable mechanical robustness and improved manageability. Notably, they exhibited a high-water absorption capacity. Moreover, these aer-ogels exhibited a sustained and favourable biological response in-vitro. They demonstrated the ability to release functional growth factors, sustaining cellular metabolic activity similar to that of conventional culture conditions, even after prolonged storage. Furthermore, they supported the adhesion and proliferation of murine fibroblasts (BALB-3T3) and the migration of Human Um-bilical Vein Endothelial Cells (HUVEC). In addition to serving as excellent matrices for cell culture, these proposed aerogels also function as efficient growth factor delivery systems. This multi-functional capability positions them as promising candidates for various tissue regeneration strategies. Importantly, the elaborated aerogels can be conveniently stored and considered as ready-to-use products, enhancing their practicality and applicability in regenerative medicine

Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote bladder cancer development directly by stimulating bladder urothelium and indirectly by suppressing immunity. We are particularly interested in natural killer (NK) cells because they are important, but often overlooked anti-cancer lymphocytes.

Entheseal spinal inflammation and new bone formation with progressive ankylosis may occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). This study evaluated whether JAK inhibition with tofacitinib modulated the key disease associated cytokines, TNF and IL-17A and whether tofacitinib also modulated bone marrow stromal cell-derived mesenchymal stem cells (MSCs) function including osteogenesis, since post inflammation new bone formation occurs in these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were in-vestigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in Tofacitinib treated (1000nM) peri-entheseal bone (PEB) and peripheral blood mononuclear cells (PBMC) following ELISA. Bone marrow stromal cell-derived mesenchymal stem cells (MSCs) colony forming unit (CFU-F) and multilineage potential was evaluated using tofacitinib (dosag-es ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cytokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by to-facitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and oste-ogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human enthe-seal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofacitinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis, the rele-vance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA.

Activated platelets are involved in blood coagulation by exposing phosphatidylserine (PS), which serves as a substrate for assembling coagulation complexes. Platelets accelerate fibrin formation and thrombin generation, two final reactions of the coagulation cascade. We investigated the effects of antiplatelet drugs on platelet impact in these reactions and platelet ability to expose PS. Washed human platelets were incubated with acetylsalicylic acid (ASA), ticagrelor, ASA in combination with ticagrelor, ruciromab (glycoprotein IIb-IIIa antagonist) or prostaglandin E1 (PGE1). Platelets were not activated or activated by collagen, sedimented in multiwell plates and plasma was added after supernatant removal. Fibrin formation (clotting) was monitored in a recalcification assay by light absorbance and thrombin generation in a fluorogenic test. PS exposure was assessed by annexin V staining using flow cytometry. Ticagrelor (alone and in combination with ASA), ruciromab and PGE1, but not ASA prolonged the lag phase and decreased the maximum rate of plasma clotting, and decreased the peak and maximum rate of thrombin generation. Inhibition was observed when platelets were not treated with exogenous agonists (activation by endogenous thrombin) and pretreated with collagen. Ticagrelor (alone and in combination with ASA), ruciromab and PGE1, but not ASA decreased PS exposure on washed platelets activated by thrombin and by thrombin + collagen. PS exposure on activated platelets in whole blood was lower in patients with acute coronary syndrome receiving ticagrelor + ASA in comparison with donors free of medications. These results indicate that antiplatelet drugs are able to suppress platelet coagulation activity not only in vitro but also after administration to patients.

Inherited platelet disorders (IPDs) are rare diseases featured by low platelet count and/or defective platelet function. Patients have variable bleeding diathesis and sometimes additional features that can be congenital or acquired. Identification of an IPD is desirable to avoid misdiagnosis of immune thrombocytopenia and use of improper treatments. Diagnostic tools include platelet function studies and genetic testing. The latter can be challenging as the correlation of its outcomes with phenotype is not easy. The immune-morphological evaluation of blood smear (by light- and immunofluorescence microscopy) represents a reliable method to phenotype subjects with suspected IPD. It is relatively cheap, not excessively time-consuming, and applicable to shipped samples. In some forms, it can provide diagnosis by itself, as for MYH9-RD, or in addition to other first-line tests as aggregometry or flow cytometry. In regard to genetic testing, it can guide specific sequencing. Since only minimal amounts of blood are needed for preparation of blood smears, it can be used to further characterize thrombocytopenia in pediatric patients and even newborns. In principle it is based on visualizing alterations in the distribution of proteins, which result from specific genetic mutations, by using monoclonal antibodies. It can be applied to identify deficiencies in membrane proteins, disturbed distribution of cytoskeletal proteins, and alpha as well as delta granules. On the other hand mutations associated with impaired signal transduction are difficult to identify by immunofluorescence of blood smears. This review summarizes technical aspects and the main diagnostic patterns achievable by this method.

Background: Since the previous study dealing with the case fatality ratio and infection fatality ratio caused by COVID-19, the author has received many comments that prompted the question: "Why did an optimistic prognosis fail?" To answer this question, a more detailed and expanded analysis was carried out in a new study. Objective: To evaluate the dynamics of monthly numbers of cases, deaths, tests and CFR worldwide during three phases of the COVID-19 pandemic. Material and Methods: Twenty three sets of databases, dated the 22nd of each month from January 2020 to November 2021, for 213 countries were collected from the Worldometer website. The number of cases, deaths, tests, CFR, IFR, etc. were counted for various periods of time for each of the 213 countries, then results related to different periods of time were compared. Results: The analysis of the main epidemiological parameters led to the division of three phases of the global pandemic evolution. The first phase (23.01.20-22.07.20), the second phase (23.07.20-22.01.21) and the third phase (23.01.21-22.07.21) were different in terms of the number of tests performed, new cases, and mortality due to COVID-19. By the end of the second phase, the worldwide statistics indicated the imminent end of the pandemic, but the third phase was characterized by a sudden rise in the number of new cases and deaths that could not be explained rationally. The most dramatic evolution of the epidemic curve occurred in the countries where doctors had successfully battled COVID-19 during the first two phases of the pandemic. Conclusions: Despite the decrease in overall death numbers during the latest months analyzed, additional study is necessary to identify the cause for the increase in the number of new cases and deaths during the third phase of the pandemic. Only complete information regarding the positive and negative impact of medical and non-medical methods of diagnostics and prophylaxis of COVID-19 can help to organize effective measures to end the current pandemic and prevent a similar one from occurring in the future. Presumably, there are several causes of the negative evolution of the current pandemic, including the overreliance on PCR tests, application of non-specialized premises for quarantine and treatment, decrease in herd and individual immunity, inadequate change of therapeutic protocols, and ignoring prophylactic treatment. It can be suggested that the use of immunemodulatory drugs, for example, thymus extract or thymic peptides, in groups of people with compromised immunity is necessary, and prophylactic and therapeutic protocols should be changed from the 'standard' types to 'personalized' ones.

The precise molecular basis of anti-tumor immunity is not yet fully understood, although commensal Bifidobacterium (c-BIF) is expected to be one of the key players in cancer control via antigenic mimicry. We investigated the sequence similarity between c-BIF and cytotoxic T lymphocyte (CTL) epitope peptides against human tumor-associated antigens to better understand the molecular basis of antigenic mimicry. We used two different similarity analyses for this purpose, a linear sequence analysis and a similarity analysis of T cell receptor (TCR)-mediated recognition of CTL epitope peptides on antigen-presenting cells. The linear sequence analysis revealed 3,900 positive numbers of similarity sites between them with 126 mean per peptide and 107 median per peptide, while the TCR-mediated recognition analysis revealed 5,018 positive numbers with a mean of 162 and median of 132 per peptide. These results demonstrated the existence of durable and abundant sequence similarities between c-BIF and CTL epitope peptides, suggesting that the former play a pivotal in inducing cellular and humoral immunity against the latter in the absence of cancer cells via antigenic mimicry.

Musculoskeletal disorders are increasingly prevalent worldwide, causing significant socioeconomic burdens and diminished quality of life. Notably, patellar chondropathy (PC) is among the most widespread conditions affecting the joint structures, resulting in profound pain and disability. Hyaluronic acid (HA) and platelet-rich plasma (PRP) have emerged as reliable, effective, and minimally invasive alternatives. Continuous research spanning from laboratory settings to clinical applications demonstrate the numerous advantages of both products. These encompass lubrication, anti-inflammation, and stimulation of cellular behaviors linked to proliferation, differentiation, migration, and the release of essential growth factors. Cumulatively, these benefits support the rejuvenation of bone and cartilaginous tissues, which are otherwise compromised due to the prevailing degenerative and inflammatory responses characteristic of tissue damage. While existing literature delves into the physical, mechanical, and biological facets of these products, as well as their commercial variants and distinct clinical uses, there is limited discussion on their interconnected roles. We explore basic science concepts, product variations, and clinical strategies. This comprehensive examination provides physicians with an alternative insight into the pathophysiology of PC as well as biological mechanisms stimulated by both HA and PRP that contribute to tissue restoration.

Background. IgA nephropathy (IgAN) is associated with chronic inflammation. Platelet-related parameters, such as platelet (PLT) count, platelet-to-albumin ratio (PAR) and platelet-to-lymphocyte ratio (PLR), were examined as potential prognostic indicators for renal and cardiovascular (CV) outcomes in IgAN. Methods. 150 IgAN patients were devided into two groups based on the cut-off value of PAR. All-cause mortality, major CV events and end-stage renal disease were the primary combined endpoints. Secondary endpoints, such as CV or renal endpoints, were also analyzed separately. Results. The patient’s mean age was 43.7 ± 13.5 years, and the follow-up time was 124 ± 67 months. The K-M curve showed that PLR, PAR and PLT were strongly associated with primary combined (p = 0.002, p = 0.004, p = 0.001) and renal outcomes (p < 0.001, p < 0.001, p < 0.001), but not with CV outcomes in IgAN. However, when combined with left ventricular hypertrophy (LVH) or metabolic syndrome (MetS) PAR was found to be a significant predictor of both primary (p < 0.001, p < 0.001) and secondary outcomes (p = 0.001 and p = 0.038; p = 0.001 and p = 0.015). Additionally, PLR correlated with microalbuminuria (r = -0.165, p = 0.033) and LVH (r = -0.178, p = 0.025), while PLT correlated with eGFR (r = 0.158, p = 0.040). Conclusion. Elevated PAR and PLR may predict progression to end-stage kidney disease, but in combination with LVH and MetS, they showed CV events also in IgAN. The determination of PAR and PLR can be useful and cost-effective parameters for assessing both cardiovascular and renal risks in CKD.

Training has a significative effect on physiology of blood coagulation both in humans and in horses. Several hemostatic changes have been reported after exercise in the horse but data available are inconclusive. The aim of this study was to investigate the platelet activation and primary platelet-related hemostasis modifications in young untrained Thoroughbred racehorses in the first 4-month timeframe incremental training period in order to improve knowledge on this topic. Twenty-nine clinically healthy, untrained, 2-year-old Thoroughbred racehorses. Never trained Thoroughbreds were followed during their incremental 4-month sprint exercise schedule. Blood collection was performed once a month (T-30, T0, T30, T60, and T90). Platelet aggregation was measured by light transmission aggregometer in response to various agonists: adenosine diphosphate (ADP), collagen and calcium ionophore A23187. Platelet function was evaluated using the Platelet Function Analyzer (PFA-100®) using collagen/ADP and collagen/adrenaline cartridges. Nitrite-nitrate (NOx) plasma concentrations were measured by a colorimetric assay to assess in vivo nitric oxide bioavailability. Platelet activation was investigated also through gene expression analyses (selectin P-SELP, ectonucleotidase CD39-ENTPD1, prostaglandin I2 synthase-PTGIS, endothelial nitric oxide synthase 3-NOS3). Differences among the time points were analyzed and mean±SEM were calculated. Significant modifications were identified compared with T-30 with increase of platelet aggregation (collagen:32.6±4.8 vs 21.6±4.9%; ADP: 35.5±2.0 vs 24.5±3.1%; A23187: 30±4.7 vs 23.8±4%) and a shorter closure time of C-ADP cartridges (75.6±4.4 vs 87.7±3.4 sec) that tended to return to baseline value at T90. NOx concentrations in plasma significantly increased after 30 days of training program compared with baseline. The first long-term training period induce platelet hyperactivity already after 30 days in untrained Thoroughbreds. Regular physical training blunts the negative effects of acute efforts on platelets activation.

Accidental soft tissue injuries are a frequent injury. We report a case involving a 37-year-old man with a soft tissue wound failing conservative treatment. The use of applied fibrin membranes and concentrated growth factors yielded a resolution of the injury in 16 months without need of skin grafting.

The manifold actions of the pro-inflammatory and regenerative chemokine CXCL12/SDF-1α are executed through the canonical GProteinCoupledReceptor CXCR4, and the non-canonical ACKR3/CXCR7. Platelets express CXCR4, ACKR3/CXCR7, and are a vital source of CXCL12/SDF-1α themselves. In recent years, a regulatory impact of the CXCL12-CXCR4-CXCR7 axis on platelet biogenesis i.e. megakaryopoiesis, thrombotic and thrombo-inflammatory ac-tions have been revealed through experimental and clinical studies. Platelet surface expression of ACKR3/CXCR7 is significantly enhanced following myocardial infarction (MI) in acute coro-nary syndrome (ACS) patients, also associated with improved functional recovery and progno-sis. The therapeutic implications of ACKR3/CXCR7 in myocardial regeneration and improved recovery following an ischemic episode, are well documented. Cardiomyocytes, cardi-ac-fibroblasts, endothelial lining of the blood vessels perfusing the heart, besides infiltrating platelets and monocytes, all express ACKR3/CXCR7. This review recapitulates ligand induced differential trafficking of platelet CXCR4-ACKR3/CXCR7 affecting their surface availability, and in regulating thrombo-inflammatory platelet functions and survival through CXCR4 or ACKR3/CXCR7. It emphasizes the pro-thrombotic influence of CXCL12/SDF-1α exerted through CXCR4, as opposed to the anti-thrombotic impact of ACKR3/CXCR7. Offering an innovative translational perspective, this review also discusses the advantages and challenges of utilizing ACKR3/CXCR7 as a potential anti-thrombotic strategy in platelet associated cardiovascular dis-orders, particularly in coronary artery disease (CAD) patients post-MI.

In the present study we tested the effect of small molecular weight redox molecules on collagen-induced platelet aggregation. We used N-acetylcysteine amide (AD4), the amide form of N-acetylcysteine (NAC), a thiol antioxidant with improved lipophilicity and bio-availability compared to NAC, and the thioredoxin mimetics (TXM) peptides, TXM-CB3, TXM-CB13, and TXM-CB30. All compounds significantly inhibited platelet aggregation induced by collagen, with TXM-peptides and AD4 being more effective than NAC. The levels of TxB2 and 12-HETE, the main metabolites derived from the cyclooxygenase and lipoxygenase pathways following platelet activation, were significantly reduced in the presence of AD4, TXM-peptides, or NAC, when tested at the highest concentration (0.6 mM). The effect of AD4, TXM-peptides, and NAC was tested also on the clotting time (CT) of whole blood. TXM-CB3 and TXM-CB30 showed the highest increase of CT. Furthermore, two representative compounds, TXM-CB3, and NAC, showed an increase in the an-ti-oxidant free sulfhydryl groups of plasma detected by Ellman’s method, suggesting a contribution of plasma factors to the antiaggregating effects. Our results suggest that these small molecular weight redox peptides might become useful for the prevention and/or treatment of oxidative stress conditions associated with platelet activation.

Pterygium is a common ocular disease caused by abnormal cellular proliferation leading to abnormal fibrovascular growth of the conjunctiva. The main treatment is surgical removal; however, despite the improvement of surgical techniques and development of adjuvant therapies, postoperative recurrence, which can be as high as 89%, remains a challenge. Currently, pterygium excision with conjunctival autograft remains the preferred surgical technique to decrease recurrence, especially when combined with ciclosporin eye drops. Nevertheless, there is no gold standard surgical technique to prevent pterygium recurrence. Therefore, this review aims to assess the safety, effectiveness and, applicability of platelet-rich fibrin membrane for primary pterygium surgery and assess its possible benefits in resource-limited settings.

Coffee is rich in caffeine (CF), chlorogenic acid (CGA) and phenolics. Differing types of coffee beverages and brewing procedures may result in differences in total phenolic contents (TPC) and biological activities. Inflammation and increases of platelet activation and aggregation can lead to thrombosis. We focused on determining the chemical composition, antioxidant activity and inhibitory effects on agonist-induced platelet aggregation and cyclooxygenase (COX) of coffee beverages in relation to their preparation method. We prepared instant coffee and brewed coffee beverages using drip, espresso and boiling techniques. Coffee extracts were assayed for their CF and CGA contents using HPLC, TPC using colourimetry, platelet aggregation with an aggregometer and COX activity using ELISA. The findings have shown all coffee extracts, except the decaffeinated types, contained nearly equal amounts of CF, CGA and TPC. Inhibitory effects of coffee extracts on platelet aggregation differed depending on the activation pathways induced by different agonists. All espresso, drip and boiled coffee extracts caused dose dependent inhibition of platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid (ARA). The most marked inhibition was seen at low doses of collagen or ARA. Espresso and drip extracts inhibited collagen-induced platelet aggregation more than purified caffeine or CGA. Espresso, boiled and drip coffee extracts were also a more potent inhibitors of COX-1 and COX-2 than purified caffeine or CGA. We conclude that inhibition of platelet aggregation and COX-1 and COX-2 may contribute to anti-platelet and anti-inflammatory effects of espresso and drip coffee extracts.

Blood Concentrates (BCs) are autologous non-transfusional therapeutical preparations with biological properties applied in tissue regeneration. These BCs differ in the preparation method, in fibrin network architecture, growth factors release as well as in platelet/cell content. Methodological changes result in distinct matrices that can compromise their clinical effectiveness. The present study evaluated the influence of different g-forces and types of tubes in the release of vascular endothelial growth factor (VEGF) from platelet-rich fibrin (PRF) as a function of time. The PRF-like samples were obtained with three g-forces (200, 400, and 800 x g) for 10 minutes in pure glass tubes or in polystyrene-clot activator tubes. Scanning and Transmission electron microscopy was used to morphometric analyzes of PRF’s specimens and flow cytometry was used to quantify VEGF slow release until 7 days. Our results showed that platelets were intact and adhered to the fibrin network, emitting pseudopods and in degranulation. The fibrin network was rough and twisted with exosomic granulations impregnated on its surface. An increase in the concentration of VEGF in the PRF supernatant was observed until 7 days for all g forces (200, 400 or 800 x g), with the highest concentrations observed with 200 x g, in both tubes, glass or plastic. Morphological analyzes showed a reduction in the diameter of the PRF fibers after 7 days. Our results showed that g-force interferes with the shape of the fibrin network in the PRF, as well as affect the release of VEGF stored into platelets. This finding may be useful in applying PRF to skin lesions, in which the rapid release of growth factors can favor the tissue repair process. Our observations point to a greater clarification on the methodological variations related to obtaining PRF matrices, as they can generate products with different characteristics and degrees of effectiveness in specific applications.

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, Mri) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.

The application of dry lubrication in rolling contacts is challenging due to wear. In previous studies graphene platelets applied as dry lubricants on the surfaces of angular contact ball bearings demonstrated superior properties. These specific bearings, experiencing both rolling and spinning motion, create more severe conditions for dry lubricants. The applied graphene platelets have a thickness of few graphene layers in the nm range and a diameter in the µm range. Such platelets can be produced by mechanical exfoliation from graphite. To delve deeper into the lubrication effects, investigations were carried out using a milli tribometer. In the tests, a fixed steel ball is sliding against an oscillating counterpart under defined load. During the measurements, the applied load and tangential forces on the ball are recorded to calculate the friction. In our case, a steel ball with a diameter of 6 mm was used against graphene-based films on flat bearing surfaces (axial bearing washer). Comparative investigations included nano graphite particles and fullerene as dry lubricants, in addition to graphene platelets of various staple thicknesses. To increase the adhesion of the films to the surfaces, a pre-rolling process was implemented. Afterwards, the friction on the compressed films was measured. The results indicate that the pre-rolling process effectively reduces the friction of the system. After testing, the surfaces underwent analysis using laser scanning microscopy to assess the formed films, wear, and material transfer. It has been demonstrated that the pre-rolling process leads to the formation of a very thin compacted film with surface protective properties. On the ball as counterpart, the graphene platelets generate a transfer film on the contacting surface.

Hydrogels (gels) are attractive tools for tissue engineering and regenerative medicine due to their potential for drug delivery and ECM-like composition. In this study, we use rheology to characterize GelMA/alginate gels loaded with human platelet lysate (PL). We then characterize these gels from a physicochemical perspective and evaluate their ability to transport PL proteins, their pore size, and their rate of degradation. Finally, their biocompatibility is evaluated. We describe how alginate changes the mechanical behavior of the gels from elastic to viscoelastic after ionic (calcium-mediated) crosslinking. In addition, we positively report the release of PL proteins and relate it to the degradation profile of the gels and the biocompatibility of the gels. Thus, the developed gels represent attractive substrates for both cell studies and bioactive materials.

Platelet polyphosphate (polyP) can be conveniently quantified by a recent methodological breakthrough using 4′,6-diamidino-2-phenylindole (DAPI). However, the preservation of these biological samples has not yet been standardized. In a preliminary study, possible protocols were screened, and passed protocols were further tested in this study. Pure-platelet-rich plasma (P-PRP) samples and washed platelet suspensions were prepared using blood obtained from non-smoking, healthy male donors and fixed with ThromboFix for 24 h at 4 °C. Mass polyP levels were determined using a fluorometer at wavelengths of 425 and 525 nm. Platelet polyP levels were normalized to platelet counts. Statistical analyses were performed using non-parametric tests. In platelet suspension maintained in fixed conditions at 4 °C (control), platelet polyP levels significantly decreased by 20% at and after 7 days. In contrast, platelet polyP levels in both P-PRP and washed platelet suspensions were maintained without significant reduction for up to 6 weeks by removing ThromboFix after fixation and subsequent freezing in pure water at −80 °C. Owing to the low specificity of DAPI binding and the wavelengths used, fluorometric polyP quantification is often interfered with. Our validated protocols will enable long-term preservation and high-throughput polyP quantification and could be applied to relatively large cohort studies.

Emerging data have demonstrated a strong association between the gut microbiota and the development of cardiovascular disease (CVD) risk factors such as atherosclerosis, inflammation, obesity, insulin resistance, platelet hyperactivity, and plasma lipid abnormalities. Several studies in humans and animal models have demonstrated an association between gut microbial metabolites, such as trimethylamine-N-oxide (TMAO), short-chain fatty acids, and bile acid metabolites, amino acid breakdown products, with CVD. Human blood platelets are a critical contributor to the hemostatic process. Besides, these blood cells play a crucial role in developing atherosclerosis and, finally, contribute to cardiac events. Since the TMAO, and other metabolites of the gut microbiota, are associated with platelet hyperactivity, lipid disorders, and oxidative stress, the diet-gut microbiota interactions have become an important research area in the cardiovascular field. Platelets became hyperactive in people with diabetes mellitus, sedentary lifestyle, obesity, and insulin resistance and exhibited increased sensitivity at a baseline level and in response to agonists, ultimately contributing to increased aggregation plaque development. In addition to these factors, TMAO also contributes to platelet hyperactivity. Several approaches are now suggested to reduce plasma TMAO levels, such as microbiota modulation using probiotics, prebiotics, and oral broad-spectrum antibiotics. This review describes the association between microbiota-derived metabolites and CVD development.

Background The Delta Neutrophil Index (DNI), a prodiagnostic marker for sepsis, utilizes leukocyte count. Platelet activation, similar to leukocytes, plays a crucial role in host defence against pathogens and may serve as a predictor of sepsis outcome. However, the combined evaluation of Mean Platelet Component (MPC) and DNI in assessing sepsis has been rarely used. Methods To assess the prodiagnostic validity of simultaneous utilization of DNI and MPC in cases of human febrile sepsis, we conducted measurements of cellular indices, including DNI and MPC, as well as molecular biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP). This study was carried out on patients admitted to the emergency department with suspected sepsis. Results Using a cutoff value of 2.65%, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DNI in sepsis were found to be 69%, 73.9%, 77.9%, and 64.1%, respectively. Furthermore, significant differences in DNI and MPC levels were observed between the sepsis and non-sepsis groups (6.7±7.8% versus 2.1±2.2%, P=0.000 and 26.0±1.9 g/dl versus 26.8±1.4 g/dl, P=0.002), respectively. Notably, there was a negative correlation between DNI and MPC, with the strength of the correlation varying based on the cause of sepsis. By setting the cutoff value for DNI at 6.2%, the sensitivity, specificity, and NPV improved to 100%, 80.3%, and 100%, respectively, although the PPV remained at 10.6%. Importantly, the DNI≥6.2 group exhibited a higher incidence of death (10.9%, 5/46) and multiorgan failure (19.6%, 9/46) compared to the DNI<6.2 group (0.0%, 0/46 and 0.0%, 0/167, respectively) (P=0.000 and P=0.000, respectively). Conclusions In our study, DNI demonstrates superior effectiveness compared to other molecular biomarkers such as CRP and procalcitonin in distinguishing febrile septic patients from febrile nonseptic patients and predicting prognosis. Additionally, there exists a negative correlation between MPC and DNI, making MPC a valuable marker for differentiating the etiology of sepsis. These findings hold significant clinical implications as DNI/MPC is a cost-effective and readily applicable approach in various impending sepsis scenarios. Notably, this study represents the first examination of the prodiagnostic validity of simultaneously employing DNI and MPC in human cases of febrile sepsis.

Alveolar bone atrophy after tooth extraction presents significant difficulties when planning delayed-immediate implant treatment to replace a lost tooth. Socket augmentation is an effective therapy that limits the post extraction volumetric changes and facilitates implant placement whilst reducing the need for staged grafting. However, socket augmentation and osteoconductive graft conversion is a slow process that could take 4-6 months. PRF and its variants have significant bio-enhancement effect on wound healing and regeneration through release of platelet drived growth factors, bioactive substances, cytokines. Leukocytes in PRF also play a significant role in enhancing tissue regeneration as part of osteo-immune response. Use of PRF during socket augmentation is highly effective in enhancing extraction site healing and graft integration by angiogenesis, cell proliferation, recruitment, and differentiation through release of growth factors and bioactive substances mediated by platelets and leukocytes. PRF with SA is recommended as an adjunct to SA as a sole biomaterial or in combination with xenograft or allograft bone substitutes to enhance tissue regeneration and to reduce risk of infection, osteitis and postoperative pain in extraction sockets

Platelets are a uniquely mammalian physiologic attribute. As the only non-marine vertebrate class to experience menopause, humans have a substantial post-reproductive lifespan and are believed to have a limited, non-renewable oocyte supply. Ovarian reserve typically declines after about age 35yrs, marking losses which cannot be recovered by available fertility medications. When in vitro fertilization fails due to low or absent ovarian response, gonadotropin adjustments are often ineffectual and if additional oocytes are occasionally harvested, egg quality is usually poor. This problem was confronted by Greek researchers who developed a new surgical method to insert autologous platelet-rich plasma (PRP) into ovaries; the first ovarian PRP success to improve reproductive outcomes was published from Athens in 2016. This innovation influenced later research with condensed platelet-derived growth factors, leading to correction of oocyte ploidy error, normal blastocyst development, and additional term livebirths. Yet women’s health was among the last clinical domains to explore PRP, and its role in ‘ovarian rejuvenation’ remains unsettled. One critical aspect in this procedure is platelet activation, a commonly overlooked step in the cytokine release cascade considered essential for successful transition of undifferentiated ovarian stem cells to an oocyte lineage. Poor activation of platelets thus becomes an unforced error, potentially diminishing or even negating post-treatment ovarian follicular response. To answer this query, relevant theory, current disagreements, and new data on platelet activation are presented, along with clinical challenges for regenerative fertility practice.

For their clinical use Mesenchymal Stromal Cells (MSCs), isolated from bone marrow (BM-MSCs) are considered Advanced Therapy Medicinal Products (ATMP) and need to be produced according to Good Manufacturing Practice (GMP). Human platelet lysate (HPL) represents a good GMP-compliant alternative to animal serum and after pathogen inactivation with Psoralen was more efficient and safer to produce MSCs in GMP. In this study MSCs cultivated in FBS (FBS-MSC) or inactivated HPL (iHPL-MSC), were compared for their immunomodulant properties. In particular, the effects of MSCs on: 1)proliferation of total Lymphocytes (Ly) and on naïve T Ly subsets induced to differentiate versus Th1 and Th2 Ly; 2) the immunophenotype of different T cell subsets; 3)the cytokine release to verify Th1, Th2 and Th17 polarization were analyzed by using in vitro co-culture system. We observed that iHPL-MSCs showed the same immunomodulant properties observed in the FBS-MSCs co-cultures. Although, a more efficient effect on the increase of naïve T cells and, in the Th1 cytokine release related to iHPL was observed. This study confirms that iHPL, used as medium supplement, may be considered a good alternative to FBS for a GMP-compliant MSC expansion to preserve their immunomodulant proprieties.

The eyes serve as a window into underlying physical and cognitive processes. Although factors such as pupil size have been studied extensively, a less explored yet potentially informative aspect is blinking. Given its novelty, blink detection techniques are far less available compared to eye-tracking and pupil size estimation tools. In this work, we present a new unsupervised machine learning blink detection strategy using existing eye-tracking technology. The method is compared to two existing techniques. All three algorithms make use of eye aspect ratio values for blink detection. Accurate and rapid blink detection complements existing eye-tracking research and may provide a new informative index of physical and mental status.

The figures of merit of luminescence intensity ratio (LIR) thermometry for Er3+ in 40 different crystals and glasses have been calculated and compared. For calculations, the relevant data has been collected from the literature while the missing data were derived from available absorption and emission spectra. The calculated parameters include Judd-Ofelt parameters, refractive indexes, Slater integrals, spin-orbit coupling parameters, reduced matrix elements (RMEs), energy differences between emitting levels used for LIR, absolute and relative sensitivities. We found a slight variation of RMEs between hosts as a result of variations in values of Slater integrals and spin-orbit coupling parameters, and we calculated their average values over 40 hosts. The calculations showed that crystals perform better than glasses in Er3+ based thermometry, and we identified hosts that have large values of both absolute and relative sensitivity.

In public health literature the risk of death or disease associated with a dietary, environmental of behavioral factor is most commonly denoted by odds ratio (OR), hazard ratio (HR) or risk ratio (RR). The ratio indices have several desirable statistical properties. However, the most important question is whether there are some evolved innate norms of perception of risk that people use and what they are. We conducted a simple one question survey of 98 individuals with different age, sex, educational and professional backgrounds. The respondents were asked to judge the relative perceived risk of four different hypothetical habits for which data on the percentage of people affected by the disease with and without the habit was given. They were asked to rank the risks for the four habits. Results showed that the habits that had the highest difference between probability of acquiring the disease were ranked high on risk perception. The probability ratios did not affect risk perception significantly. Further age, sex, profession or formal training in statistics did not affect the response significantly. Even individuals that were formally trained to use OR and HR as risk indicators, preferred using probability differences over ratios for judging their own risk in the perceived context. This preliminary inquiry into intuitive statistical perception suggests that designing statistical indices based on people’s innate perception may be a better strategy than trying to train people to understand the indices designed by expert statisticians.

This paper considers estimating the ratio of two distributions with different parameters and common supports. We consider a Bayesian approach based on the Log--Huber loss function which is resistant to outliers and useful to find robust M-estimators. We propose two different types of Bayesian density ratio estimators and compare their performance in terms of Bayesian risk function with themselves as well as the usual plug-in density ratio estimators. Some applications such as classification and divergence function estimation are addressed.

The impact of the agriculture net carbon effect is crucial for climate change mitigation, yet research on this topic in China is currently insufficient. In this study, the carbon balance ratio (CBR) is used to characterise the net carbon effect of agriculture, and the spatial Durbin model and threshold regression model were used to empirically analyse the CBR with a sample of 30 provincial-level regions in China from 2004 to 2019. The aim was to investigate the mechanism of the influence of the land management scale (SCALE) of farming on the CBR. The results of the study indicate that national farming generally has a net sink effect, with large changes in interannual fluctuations; the expansion of SCALE has an obvious role in increasing sinks and reducing emissions, and has a positive spatial spillover effect on CBR, with significant spatial heterogeneity. Furthermore, as the SCALE expands, the direction of the influence of rural residents’ income and education level on CBR changes in the opposite direction, showing a significant non-linear relationship characteristic. However, in most areas, the SCALE threshold has not yet been reached, suggesting that the improvement in education levels can still offset the negative impact of economic income growth in the short term. The study recommends paying attention to the role of farmers’ human capital, changing production methods, and implementing carbon peaking and carbon neutrality goals to enhance the net sink effect of the farming industry, which would be achieved by increasing land management scale.

Nitrogen (N) strongly affects plant growth and metabolism. For shikonin biosynthesis, although the ammonium toxicity phenomenon has been reported, the effects of nitrogen on the shikonin synthesis remains obscure. In this study, we carried out four different concentrations of NH4+ treatments on Arnebia euchroma hairy roots (AEHR) to clarify the influence of NH4+ on the growth and shikonin accumulation in A. euchroma and the possible mechanism. The results showed that compared with the 0% NH4+ treatment (only nitrate as nitrogen source), 10% NH4+ treatment increased the fresh weight and the dry weight of AEHR, and promoted the synthesis of shikonins; 20% NH4+ treatment started to show the inhibition effects on growth and shikonin accumulation of AEHR and 30% NH4+ treatment exhibited the strongest inhibition effects. With increased percentage of NH4+, AEHRs became shorter and thicker with more branches. To further elucidate the mechanism, we analyzed the time-course of nitrogen assimilation, gene expression level of key enzymes involved in the shikonin biosynthesis pathway, and contents of various endogenous hormones under NH4+ toxicity condition. Results indicated that auxin and cytokinin might regulate the growth and architecture of AEHR under NH4+ toxicity, and jasmonate level was reduced along with the inhibition of shikonin biosynthesis. This first comprehensive investigation into the effects of ammonium/nitrate ratio on shikonin biosynthesis not only provided valuable data for optimizing the in vitro culture and shikonin production in A. euchroma, but also suggested potential fertilizer strategies for its cultivation.

The temporal evolution of pandemics described by the susceptible-infectious-recovered (SIR)-compartment model is sensitively determined by the time dependence of the infection (a(t)) and recovery (u(t)) rates regulating the transitions from the susceptible to the infected and from the infected to the recovered compartment, respectively. Here approximated SIR-solutions for different time dependencies of the infection and recovery rates are derived which are based on the adiabatic approximation assuming time-dependent ratios k(t)=u(t)/a(t) varying slowly in comparison to the typical time characteristics of the pandemic wave. For such slow variations the available analytical approximations from the KSSIR-model, valid for a stationary value of the ratio k, are used to insert a-posteriori the adopted time-dependent ratio of the two rates. Instead of investigating endless different combinations of the time dependencies of the two rates a(t) and u(t) a suitably parameterized reduced time dependence of the ratio k(tau) is adopted. Together with the definition of the reduced time this parameterized ratio k(tau) allows us to cover a great variety of different time dependencies of the infection and recovery rates. The agreement between the solutions from the adiabatic approximation in its four different studied variants and the exact numerical solutions of the SIR-equations is remarkably good providing strong confidence in the accuracy of the proposed adiabatic approximation.

Platelet and fibrin-rich orthobiologic products, such as autologous platelet concentrates, have been extensively studied and appreciated for their beneficial effects in multiple conditions. PRP and its derivatives, including PRF, have demonstrated encouraging outcomes in clinical and laboratory settings, particularly in the treatment of musculoskeletal disorders such as OA. Although PRP and PRF have distinct characteristics, they share similar properties. The relative abundance of platelets, peripheral blood cells and molecular components in these orthobiologic products stimulate numerous biological pathways. These include inflammatory modulation, augmented neovascularization, and delivery of pro-anabolic stimuli that regulate cell recruitment, proliferation, and differentiation. Furthermore, the fibrinolytic system, which is sometimes overlooked, plays a crucial role in musculoskeletal regenerative medicine by regulating proteolytic activity and promoting the recruitment of inflammatory cells and MSCs in areas of tissue regeneration, such as bone, cartilage, and muscle. PRP acts as a potent signaling agent; however, it diffuses easily, while the fibrin from PRF offers a durable scaffolding effect that promotes cell activity. The combination of fibrin with hyaluronic acid, another well-studied orthobiologic product, has been shown to improve its scaffolding properties, leading to more robust fibrin polymerization. This supports cell survival, attachment, migration, and proliferation. Therefore, the administration of the "power mix" containing HA and autologous PRP + PRF may prove to be a safe and cost-effective approach in regenerative medicine.

Oral mucositis is most frequently a toxic effect of chemotherapeutic and/or radiotherapeutic treatment, resulting from complex multifaceted biological events involving DNA damage. The clinical manifestations have a negative impact on the life quality of cancer patients. Preventive measures and curative treatment of mucositis are still not well established. The glycine has anti-inflammatory, immunomodulatory and cytoprotective actions, being a potential therapeutic in mucositis. The objective was to evaluate the effects of glycine on the expression of collagen and growth factors, platelet and epidermal in oral mucositis. The mucositis of which was induced by the protocol of Sonis. 40 hamsters were used, divided into two groups: Group I- control; Group II- supplemented with 5% intraperitoneal glycine, 2,0 mg/g diluted in hepes. Histopathological sections were used to perform the immune-histochemical method, the evaluation collagen expression and the growth factors: EGF and PDGF. It was observed that the group supplemented with glycine higher amounts of collagen expression and predominance type of collagen I. The glycine group presented lower immunoexpression of the growth factors, EGF and PDGF. The group supplemented with glycine showed a marked healing process of the oral mucosite, demonstrated by the predominance of collagen type I and reduction of growth factors, EGF and PDGF.

On the basis of the golden ratio and the compasseses, every angle was divided into three equal parts. In general, it has been proven that the problem of triangulation of an angle cannot be solved on the basis of the golden ratio and the expanding of the angle. The relationship of golden relativity with Pi number and Euler's number has not been investigated to solve impossible problems. According to the investigation of events in six-dimensional space-time, with the simultaneous movement of two arms of the compasses based on the golden ratio, every angle was divided into three equal parts. The growth rate based on the golden ratio is the key to solving the most intractable mathematical and physical problems.

1) Background: Ultrasound-based strain imaging is now available in several ultrasound (US) scanners. Strain ratio (SR) can be used to quantify strain recorded simultaneously in two different user-selected areas, ideally exposed to the same amount of stress. The aim of this study was to evaluate SR variability when assessed in an in-vitro setup with a tissue-mimicking phantom, on resected tissue samples and in live tissue scanning with endoscopic applications. 2) Material and methods: Retrospective analysis of SR for quantification of elastic contrasts in a tissue-mimicking phantom containing four homogenous inclusions, in 38 resected bowel wall lesions and in 48 focal pancreatic lesions examined in vivo. Median SR and the inter-quartile range (IQR) was calculated on all external and endoscopic US-applications. The IQR/median provides a measure of the SR variability focusing on the two percentiles of the data closest to the median value. 3) Results: The overall variability of SR was lowest in a tissue-mimicking phantom (mean QR/median SR: 0.07). In resected bowel wall lesions representing adenomas, adenocarcinomas or Crohn lesions, the variability increased (mean IQR/Median: 0.62). During an endoscopic examination of focal pancreatic lesions in vivo, the variability increased further (mean IQR/Median: 2.04). 4) Conclusion: SR variability increased when assessed on different targets with growing heterogeneity and biological variability as one moved from homogeneous media to live tissues and endoscopic application. This may indicate a limitation for the accuracy SR evaluation in clinical applications.

An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-κB, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

Tooth extraction is the most common procedure in dental practice. However, in the long term, it may cause alveolar ridge atrophy. This systematic review aimed to evaluate the role of platelet-rich fibrin (PRF) in post-exodontic alveolar ridge preservation in terms of its effectiveness in the regeneration of bone tissue as assessed by imaging and its efficacy compared to physiological bone healing. The study is presented in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. This systematic review was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Science Direct. The grey literature search was conducted in the New York Academy of Medicine Grey Literature Report. All the studies in this systematic review were randomized controlled trials (RCTs). The risk of bias was performed according to the Cochrane Handbook for Systematic Reviews of Interventions 6.2 (RevMan 6.2). Considering the inclusion and exclusion criteria, we included 17 randomized clinical trials, published up to 2022 investigating the efficacy of PRF in post-exodontic bone regeneration. Based on the results of clinical studies, it can be stated that despite not being statistically significant, PRF promotes neoformation and prevents bone loss between three and four months post-extraction.

Background: Obtaining adipose-derived stem cells is limited by its capacity to differentiate. Stimulation by platelet-rich fibrin appears to have the beneficial effects to accelerate differentiation. Objective: To obtain immunohistochemistry evidence of platelet-rich fibrin to accelerate differentiation of adipose-derived stem cells. Methods: We used post-test only controlled-group design. Adipose-derived stem cells were isolated and cultured until 4 passages in α-MEM culture medium. Results: GATA-4 expression increased in platelet-rich fibrin group compared with control group (68.20±6.82 vs 58.15±1.23 counts; p<0.05; 68.20±6.82 vs 52.96±2.02 counts; p<0.05). Troponin expression also increased in platelet-rich fibrin group (50.66±7.2 vs 10.73±2.39 counts; p<0.05; 50.66±7.2 vs 26.00±0.4 counts; p<0.05). Conclusion: There is an immunohistochemistry benefit of platelet-rich fibrin to accelerate differentiation of adipose-derived stem cells into cardiomyocyte-like cells.

Applying of blood biopolymers to regulate the phase composition is promising in designing the hydroxyapatite-based hybrid biomaterials with controllable resorbability. Hybrid materials based on hydroxyapatite and platelet-poor plasma (PPP) were formed in conditions of chemical precipi-tation at pH 11, [Ca2+] / [PO43–] ratio 1.67, PPP volume fraction of 6–24%, maturing time of 4–9 days. Mineral component of the materials was represented as 53% hydroxyapatite / 47% amor-phous calcium phosphate after 4 days of maturation, and 100% hydroxyapatite after 9 days of maturation. Varying PPP content from 6% to 24% provided forming of materials with rather de-fined content of amorphous calcium phosphate and biopolymer component, having desired mor-phology ranging from typical apatitic conglomerates to hybrid apatite-biopolymer fibers. Co-precipitated hybrid materials based on hydroxyapatite and PPP are promising for bone regen-eration in osteoplastic and maxillofacial applications.

B and T lymphocytes demonstrate important alterations in patients with Systemic Lupus Erythematous (SLE), with significant up-regulation of Double Negative (DN) B cells. Aim of this study was to evaluate correlation of T cell immunity changes with the distinct B cell-pattern SLE. In the present study, Flow cytometry was performed in 30 patients with SLE, on remission, and 31 healthy controls, to detect DN B cells (CD19+IgD-CD27-) and a wide range of T lymphocyte subpopulations, based on the presence of CD45RA, CCR7, CD31, CD28, CD57, defined as naive, memory and advanced differentiated/senescent T cells. Both B and T lymphocytes were significantly reduced in SLE patients. However, the percentage of DN B cells were increased, compared to HC, 12.9(2.3-74.2) vs. 8(1.7-35), p=0.04. Distribution of CD4 and CD8 lymphocytes demonstrated a shift to advanced differentiated subsets. The population of DN B cells had significant positive correlation with most of early differentiated T lymphocytes, CD4CD31+, CD4CD45RA+CD28+, CD4CD45RA+CD57-, CD4CD45RA-CD57-, CD4CD28+CD57-, CD4CD28+CD57+, CD4 CM, CD8 CD31+, CD8 NAÏVE, CD8CD45RA-CD57-, CD8CD28+CD57-, CD8CD28+CD57+. Multiple Regression analysis revealed CD4CD31+, CD8CD45RA-CD57- and CD8CD28+CD57- cells as independent parameters contributing to DN B cells, adjusted R2=0.534, p<0.0001. The predominance of DN B cells in patients with SLE is closely associated with early differentiated T lymphocyte subsets, indicating a potential causality role of DN B cells in T lymphocyte activation.

Background: In trials using normofractionated regimen, the radiation-induced lymphocyte apoptosis (RILA) and the chromosomal damage assays (CDA) have shown prognostic roles of radiation-induced adverse events. The main objectives here were to validate RILA and CDA in extreme and moderate hypofractionation regimens for breast (FAST) and prostate (CHHiP) cancers. Methods: Blood samples were collected from 400 volunteers included in FAST and CHHiP trials. The primary endpoints (PE) were first change in photographic breast appearance and first grade ≥2 RTOG bladder or bowel toxicity (BBT) in FAST and CHHiP, respectively. The secondary endpoints was first grade ≥2 breast clinical changes (BCC) in FAST and BBT using different scales in CHHiP. Results: 103 FAST and 297 CHHiP patients with lab and clinical data were included. In FAST trial, no significant association of RILA with the primary endpoint was observed. A significant association of higher RILA levels with lower risk of any RIAE was found. The risk of developing grade ≥2 RIAE decreased significantly for patients with RILA≥24% compared to those with RILA≤16% with a HR of 0.50 (95%CI 0.25-1.00, p=0.012). Concerning chromosomic aberrations, no significant associations were found with change in photographic breast appearance nor with the secondary endpoint of any RIAE. In CHHiP trial, a decreased risk of grade≥2 RTOG bladder or bowel RIAE was observed for increasing values of RILA (HR 0.97, 95%CI 0.94-1.01, p=0.11) but did not reach statistical significance. Concerning chromosomic aberrations, we found significant association of higher levels of micronuclei per cell with lower risk of gr2+ RTOGAE (p=0.021 for trend test across tertiles; p=0.023 for upper vs lower tertile). Conclusions: This study is the first to evaluate RILA and CDA as predictors of late effects after breast and prostate RT in the “hypofractionation” era. Development of toxicity biomarkers whatever the RT fractionation are urgently needed.

A new approach to the measurement with elastic lidar of depolarization produced by atmospheric aerosols is presented. The system uses two different telescopes: one for depolarization measurements and another for total-power measurements. The system architecture and principle of operation are described. The first experimental results are also presented, corresponding to a collection of atmospheric conditions over the city of Barcelona.

Choroid plexus insufficiency or glymphatic stasis are often classified as prequels to harmful accretion of toxic proteins in neurodegenerative disease. Cognitive decline and memory loss subsequently become cardinal features of Alzheimer’s disease (AD), typically progressing with amyloid-ß and tau protein accumulation. For Parkinson’s disease (PD), α-synuclein deposits and dopamine depletion are linked to impaired movement, resting tremor, and rigidity. Importantly, both diagnoses are accompanied by hyperinflammation and intrathecal cytokine changes. Thus far, numerous clinical trials for investigational drugs have produced nothing effective for AD or PD, yet the anti-inflammatory and regenerative potential of platelet-rich plasma (PRP) remains largely unexamined in this context. This report explores a proposed Phase I study on intrathecal condensed plasma growth factors processed from autologous thrombin-activated PRP as monotherapy for AD or PD. The concept gains support from related work where cytokines of platelet origin successfully lowered inflammation, corrected background fibrosis, deactivated abnormal cells, and recovered local tissue function—all desirable outcomes in AD and PD. PRP-mediated effects on membrane potentials, electrolyte balance, and water clearance are less well characterized, but experimental evidence suggests these pathways could likewise influence glymphatic drainage to ameliorate proteinopathies. As a well-tolerated ‘orthobiologic’ with no hypersensitivity risk, intrathecal PRP and its derivatives bring advantages distinct from synthetic pharmaceuticals. If age-associated neuroinflammation in AD and PD is an upstream event contributing to neural disruption, then dampening local oxidative stress by a patient’s own platelet cytokines (as already proven in other tissues) could offer therapeutic relevance to these neurodegenerative conditions as well.

Background: The proportion of dietary protein may play a key role in the development of obesity in children and adolescents. Methods: Cross-sectional data of 4,336 children and adolescents from the National Health and Nutrition Survey (NHANES) during 2011 to March 2020 were analyzed. Multivariate logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals, and restriction cubic spline was uesd to explore nonlinear relationships of dietary protein energy supply ratio and obesity in children and adolescents. Results:In the adjusted logistic regression model, for every 1% increase in dietary protein energy ratio in children and adolescents, the increased risk of obesity was 4% (OR=1.04,95%CI:1.01-1.08). The restrictive cubic spline showed a nonlinear relationship between dietary protein energy ratio and obesity in children aged 6-11 years (P <0.05). The dietary protein energy supply ratio was included in the logistic regression model after converting to quartiles into categorical variables. The adjusted OR of children aged 6-11 years was 2.08 (95%CI:1.34, 3.23,P <0.01) for the highest quartile of dietary protein energy supply ratio compared with the lowest quartile. Conclusion: In American children, dietary protein energy supply ratios was positively correlated with obesity, independent of individual characteristics and energy.

During the last forty years, the use of strontium isotopes in archaeology and biogeochemical research has spread widely. These isotopes, alone or in combination with others, can contribute to trace past and present environmental conditions. However, the interpretation of the isotopic values of strontium is not always simple and requires good knowledge of geochemistry and geology. This short paper on the use of strontium isotopes is aimed at those who use this tool (archaeologists, but not only) but who do not have a thorough knowledge of mineralogy, geology, and geochemistry necessary for a good understanding of natural processes involving these isotopes. We report basic knowledge and suggestions for a correct use of these isotopes. The isotopic characteristics of bio-assimilable strontium depend not so much on the isotopic characteristics of the bulk rock as, rather, on that of its more soluble minerals. Before studying human, animal and plant remains, the state of conservation and any conditions of isotopic pollution should be carefully checked. Samples should be collected according to random sampling rules. The data should be treated by a statistical approach. To make comparisons between different areas, it should be borne in mind that the study of current soils can be misleading since the mineralogical modification of the soil over time can be very rapid.

The Golden ratio is an irrational number that has a tendency to appear in many different scientific and artistic fields. It may be found in natural phenomena across a vast range of length scales; from galactic to atomic. In this review, the mathematical properties of the Golden ratio are discussed before exploring where in nature it has been found; beginning at astronomical scales and progressing to smaller lengths, until reaching those of atomic and quantum physics. In making such a tour across length scales, it is illustrated just how prevalent this single number is within the natural universe.

Aquaculture contributes to the sustainable development of food security, marine resource conservation, and economy. Shifting aquaculture feed from fish meal and oil to terrestrial plant-derivatives may result in cost savings. However, many carnivorous fish cannot be sustained on plant-derived materials, necessitating the need for the identification of important factors for farmed fish growth and to investigate whether components derived from terrestrial plants can be used in feed. Herein, we focused on the carnivorous fish leopard coral grouper (P. leopardus) to identify the essential growth factors and clarify their intake timing from feeds. Furthermore, we evaluated the functionality of starch, which are easily produced by terrestrial plants. Results reveal that carbohydrates, which are not considered essential for carnivorous fish, can be introduced as a major part of artificial diet. The development of artificial feed using starch offers the possibility of increasing the growth of carnivorous fish in aquaculture.

Extreme-mass-ratio inspirals (EMRIs) are significant observational targets for spaceborne gravitational wave detectors, namely, LISA, Taiji, and Tianqin, which involve the inspiral of stellar-mass compact objects into massive black holes with a mass range of approximately 104∼107M⊙. EMRIs are estimated to produce long lived gravitational wave signals with more than 105 cycles before plunge, making them an ideal laboratory for exploring the strong-gravity properties of the spacetimes around the MBHs, stellar dynamics in galactic nuclei, and properties of the MBHs itself. However, the complexity of the waveform model, which involves the superposition of multiple harmonics, as well as the high-dimensional and large-volume parameter space, make the fully coherent search challenging. In our previous work, we proposed a 10-dimensional search using Particle Swarm Optimization (PSO) with local maximization over the three initial angles. In this study, we extend the search to an 8-dimensional PSO with local maximization over both the three initial angles and the angles of spin direction of the MBH where the latter contribute a time independent amplitude to the waveforms. Additionally we propose a 7-dimensional PSO search by using a fiducial value for the initial orbital frequency and shifting the corresponding 8-dimensional Time Delay Interferometry responses until a certain lag returns the corresponding 8-dimensional log-likelihood ratio maximum. The reduced dimensionality likelihoods enable us to successfully search for EMRI signals with duration of 0.5 years and signal-to-noise ratio of 50 within a wider search range than our previous study. We discuss further developments, such as using a hierarchical search to narrow down the search ranges of certain parameters, and applying Graphics Processing Units to speed up the code. These advances aim to improve the efficiency and accuracy of the EMRI search algorithm.

The objective of this study is to assess the hepatic/renal and splenic/renal echointensity ratios in ultrasonography in patients with and without diabetic nephropathy. This retrospective study included patients with diabetes mellitus who underwent ultrasound examinations at our hospital between January 2023 and May 2023. Ultrasound examinations done with renal cortical echogenicity and cortico-medullary differentiation by using B-mode ultrasonography. The hepatic/renal and splenic/renal echo intensity ratios were compared among study groups (diabetic patients with diabetic nephropathy and without nephropathy). The diabetic nephropathy group exhibited significantly higher right renal echointensity and left renal echointensity compared to the non-nephropathic group. Additionally, the splenic/renal echointensity ratio and hepatic/renal echointensity ratio were significantly lower in the diabetic nephropathy group. Urinary microalbumin levels was significantly correlated with Right renal echointensity (r=0.65, p&lt;0.001) and Left renal echointensity (r=0.69, p&lt;0.001). There was also a significant inverse correlation between urinary albumin and splenic/renal echointensity ratio (r=-0.58, p&lt;0.001). Ultrasonography, specifically the assessment of hepatic/renal and splenic/renal echointensity ratios, shows promise as a non-invasive and cost-effective method for evaluating morphological changes in the kidneys in patients with diabetic nephropathy. These findings suggest that ultrasonography can be a valuable tool for monitoring the progression of diabetic nephropathy and contributing to its early detection and management.

We consider a model of predator-prey interaction at fractional-order where the predation obeys the ratio-dependent functional response and the prey is linearly harvested. For the proposed model, we show the existence, uniqueness, non-negativity as well as the boundedness of the solutions. Conditions for the existence of all possible equilibrium points and their stability criteria, both locally and globally, are also investigated. The local stability conditions are derived using the Magtinon's theorem, while the global stability is proven by formulating an appropriate Lyapunov function. The occurance of Hopf bifurcation around the interior point is also shown analytically. At the end, we implement the Predictor-Corrector scheme to perform some numerical simulations.

As a renewable industrial crop, Miscanthus offers numerous advantages, namely high photosynthesis activity (as a C4 plant) and exceptional CO2 fixation rate. These properties make Miscanthus very attractive for industrial exploitation, such as lignin generation. Here, we present a systematic study analyzing the correlation of the lignin structure with Miscanthus genotype and plant portion (stem versus leaf). Specifically, the ratio of the three monolignols and corresponding building blocks as well as the linkages formed between the units have been studied. Depending on the Miscanthus genotype and plant component (leaf versus stem), correlations between chemical structure and properties of the lignins have been determined, i.e. correlations in molecular weight, polydispersity and decomposition temperature. Lignin isolation was performed using non-catalyzed organosolv pulping and the structure analysis includes NREL, FTIR, UV-Vis, HSQC-NMR, TGA, pyrolysis GC/MS. Structural differences were found for stem and leaf-derived lignins. Compared to beech wood lignins, Miscanthus lignins possess lower molecular weight and narrow polydispersities (< 1.5 Miscanthus vs. > 2.5 beech) corresponding to improved homogeneity. In addition to conventional univariate analysis of FTIR spectra, multivariate chemometrics revealed distinct differences for aromatic in-plane deformations of stem versus leaf-derived lignins. These results emphasize the potential of Miscanthus as low-input resource and Miscanthus-derived lignin as promising agricultural feedstock.

Background: Antiplatelet medications such as aspirin and clopidogrel are used following thrombotic stroke or transient ischemic attack (TIA) to prevent a recurrent stroke. However, the antiplatelet treatments fail frequently, and patients experience recurrent stroke. One approach to lower the rates of recurrence, may be the individualized antiplatelet therapies (antiplatelet therapy modification (ATM)) based on the results of platelet function analysis (PFA). This review was undertaken to gather and analyse the evidence about the effectiveness of such approaches. Methods: We searched Medline, CINAHL, Embase, Web of Science and Cochrane databases to 7 January 2020. Results: Two observational studies involving 1136 patients were included. The overall effects of PFA-based ATM on recurrent strokes (OR 1.05; 95% CI 0.69 to 1.58), any bleeding risk (OR 1.39; 95% CI 0.92 to 2.10) or death hazard from any cause (OR 1.19; 95% CI 0.62 to 2.29) were not significantly different from the standard antiplatelet therapy without ATM. Conclusions: The two studies showed opposite effects of PFA-guided ATM on the recurrent strokes in aspirin non-responders, leading to an insignificant difference in the subgroup meta-analysis (OR 1.59; 95% CI 0.07 to 33.77), while the rates of any bleeding events (OR 1.04; 95% CI 0.49 to 2.17) or death from any cause (OR 1.17; 95% CI 0.41 to 3.35) were not significantly different between aspirin non-responders with ATM and those without ATM. There is a need for large randomized controlled trials which account for potential confounders such as ischemic stroke subtypes, technical variations in the testing protocols, patient adherence to therapy, and pharmacogenetic differences.

In the human organism various carotenoids are present of which, some are retinoid precursors. The bioactive derivatives of these retinoids are the retinoic acids, which can potently activate nuclear hormone receptors like the retinoic acid receptor and the retinoid X receptor. In our study using an HPLC analytical approach we aimed to assess how plasma carotenoid and retinoid concentrations along with the ratio of their isomers are altered in atopic dermatitis (AD) patients (n=20) compared to healthy volunteers (HV, n=20). We found that plasma levels of the carotenoids lutein (HV 198 ± 68 ng/ml, AD 158 ± 57 ng/ml), zeaxanthin (HV 350 ± 142 ng/ml, AD 236 ± 85) as well as the retinoids retinol (HV 216 ± 89 ng/ml, AD 167 ± 76 ng/ml) and all-trans-retinoic acid (HV 1.1 ± 0.6 ng/ml, AD 0.7 ± 0.5 ng/ml) were significantly lower in AD-patients, while lycopene, α-carotene and β-carotene levels were comparable. In addition the ratios of 13-cis vs. all-trans lycopene as well as 13-cis vs. all-trans retinoic acid were increased in the plasma of AD-patients indicating an AD-specific 13C-isomerisation. A positive correlation with SCORRAD was calculated with 13-cis vs. all-trans lycopene ratio, while a negative correlation was observed with zeaxanthin plasma levels. Based on our results we conclude that in the plasma of AD-patients various carotenoids and retinoids are at lower levels, while the ratio of lycopene isomers was also altered. The higher rate of lycopene and retinoic acid isomerisation products might be a consequence of AD or might result in an altered activation of nuclear hormone receptor signaling pathways and thus maybe partly be responsible for the AD-phenotype and additionally may represent a good plasma marker for AD.

In the first wave of COVID-19, up to 20% of patients had skin lesions with variable characteristics. There is no clear evidence of the involvement of the SARS-CoV-2 virus in all the cases; some of these lesions may be secondary to drug hypersensitivity. To analyze the possible cause of the skin lesions, we performed a complete allergology study on 11 patients. One year after recovery from COVID-19, we performed a lymphocyte transformation test (LTT) and Th1/Th2 cytokine secretion assays of PBMC. We included 5 nonallergic patients treated with the same drugs without lesions. Except for one patient who had an immediate reaction to azithromycin, all patients had a positive LTT to at least one of the drugs tested (azithromycin, clavulanic acid, hydroxychloroquine, lopinavir, and ritonavir). None of the nonallergic patients had a positive LTT. We found mixed Th1/Th2 cytokine secretion (IL-4, IL-5, IL-13, and IFN-γ) in patients with skin lesions corresponding to mixed drug hypersensitivity type IVa and IVb. In all cases, we identified a candidate drug as the culprit for skin lesions during SARS-CoV-2 infection, although only three patients had a positive drug challenge. Therefore, it would be reasonable to recommend avoiding the drug in question in all cases.

Background: Maternal mortality (MM) is a matter of serious concern in low income developing countries (LDCs). Perspective: A great reduction has been observed regarding the maternal deaths globally after huge efforts since 1990 todate. However, the situation continues to be either stagnant or worsening in developing countries, suggesting that the efforts to cope with this issue are either insufficient or not properly implemented. We need to first diagnose the problem areas that are a great hurdle in the road to success towards the reduction of MM. Postpartum haemorrhage and preeclampsia are one of the most common causes of MM. Malnutrition, neurological dysfunction and cancer are among the non-obstetric causes. Trained medical and paramedical staff can be of great help in this regard by increasing awareness among masses at grass root level. Target set by Millennium Development goal has minimized the MM by 44%. But it has not met the target set by Millenium Development Goals 5 and a lot of measures need to be taken in this regard. Conclusions: Majority of the MDs are preventable and can be avoided by adopting appropriate frameworks, linked data sets, surveillance, birth attendants training, preparation for births, etc. Delay in decision to get healthcare, access to healthcare center and receiving these facilities are the main factors in MM.

For a hierarchy of large scale structures, like galaxies, galaxy clusters, super-clusters, etc. the requirement that their gravitational (binding) self-energy density must at least equal or exceed the background repulsive dark energy density implies a universal mass-radius relation given by M/R² ~ 1g/cm². Here we point out that this mass-radius relation also holds for important individual biological structures, and even various organisms as a whole such as humans, trees, and to behemoths like whales, even though the physics is different. Here we try to understand this universality from two different physical considerations. We also point out the coincidence that the densities of most biological entities are close to that of water, and that the average density of main-sequence stars and giant planets are close to this density. We give a physical basis for the same.

In the paper, by virtue of some properties for the Riemann zeta function, the author finds a double inequality for the ratio of two consecutive Bernoulli numbers with even indexes and analyzes the approximating accuracy of the double inequality.

Analytical channel design tools have not advanced appreciably in the last decades, and continue to produce designs based upon a single representative discharge that may not lead to overall sediment continuity. It is beneficial for designers to know when a simplified design may be problematic and to efficiently produce alternative designs that approximate sediment balance over the entire flow regime. The Capacity/Supply Ratio (CSR) approach, an extension of the Copeland method of analytical channel design for sand channels, balances the sediment transport capacity of a design reach with the sediment supply of a stable upstream reach over the entire flow duration curve (FDC) rather than just a single discharge. Although CSR has a stronger physical basis than previous analytical channel design approaches, it has not been adopted in practice because it can be a cumbersome and time-consuming iterative analysis without the use of software. We investigate eighteen sand-bed rivers in a comparison of designs based on the CSR approach and five single-discharge metrics: the effective discharge (Qeff), the 1.5-year recurrence interval discharge (Q1.5), the bankfull discharge (Qbf), and the discharges associated with 50th (Qs50) and 75th (Qs75) percentiles of the cumulative sediment yield curve. To facilitate this analysis we developed a novel design tool using the Visual Basic for Applications (VBA) programming language in Excel® to produce stable channel slope-width combinations based on the CSR methodology for both sand- and gravel-bed streams. The CSR Stable Channel Design Tool’s (CSR Tool) code structure was based on Copeland’s method in SAM and HEC-RAS (Hydrologic Engineering Center’s River Analysis System) and was tested with a single discharge to verify outputs. The Qs50 and Qs75 single-discharge designs match the CSR output most closely, followed by the Qbf, Qeff, and Q1.5. The Qeff proved to be the most inconsistent design metric because it can be highly dependent on the binning procedure used in the effectiveness analysis. Furthermore, we found that the more rigorous physical basis of the CSR analysis is potentially most important in designing ‘labile’ channels with highly erodible substrate, high perennial flow ‘flashiness,’ low width-to-depth ratio, and high incoming sediment load. The CSR Tool provides a resource for river restoration practitioners to efficiently utilize in-depth design techniques that can promote sediment balance in dynamic fluvial systems.

Ticks are one of the most dominant forced ectoparasites of vertebrates, belonging to the arthropods, which transmit pathogens such as bacteria, viruses, and parasites to humans and animals in Iran and worldwide. Given that, sex ratio factors can affect the epidemiology of vector-borne diseases, this study aimed to identify and determine the ticks' sex ratio and host type (camels, sheep, cattle, dogs, chickens, and pigeons) in different areas of Tehran province. This descriptive cross-sectional study took samples from different animal body parts in four seasons from 20 villages in 2019, in which 685 hard ticks and 121 soft ticks were caught from 1623 studied livestock and poultry. Regarding sex segregation among all caught ticks, 42.01% were male, and 57.99% were female. It is noteworthy that in both mountain and plain environments, R. sanguineus species of hard ticks had the most elevated sex ratio. Most ticks were collected from sheep hosts with 60.04% and the lowest from cattle hosts with 0.62% in tick infestation.

A developed six-port reflectometry (SPR) system was integrated to measure the relative permittivity of tumor and normal breast tissue for medical diagnostic purpose. In order to obtain an accurate and precise measurement, the calibration process was done to the SPR using the well-known three-standard technique. Next, the studied dielectric probe was connected to the calibrated measurement-port of the SPR. The open end of the probe aperture was dibbed into the normal and tumor synthetic breast tissue samples to measure the synthetic breast tissues dielectric constant, ɛrʹ, and loss factor, ɛrʺ in the frequency range of 1.5 GHz to 3.3 GHz. Finally, the comparative studies were conducted between commercial VNA with Keysight 85070E dielectric probe and the studied SPR-probe system based on the measured magnitude of the reflection coefficient, phase shift, dielectric constant, and loss factor of the synthetic breast samples. The maximum absolute errors of the measured reflection coefficient magnitude, phase shift, dielectric constant, and loss factor were found to be 0.01, 1.07°, 1.12, and 0.75, respectively. It was ascertained that the predicted dielectric constant, ɛrʹ, is able to differentiate between normal, (ɛrʹ &lt; 50) and tumor, (ɛrʹ &gt; 50) breast tissues.

Background: As cancer progresses, cells acquire traits that allow them to disperse and disseminate to distant locations in the body – a process known as metastasis. While in the vasculature, these cells are referred to as circulating tumour cells (CTCs) and can manifest either as single cells or clusters of cells (i.e., CTC clusters), with the latter being the most aggressive. The increased metastatic potential of CTC clusters is generally associated with cooperative group benefits in terms of survival, such as increased resistance to shear stress, anoikis, immune attacks and drugs. However, the adoption of a group phenotype poses a challenge when exiting the vasculature (extravasation) as the large size can hinder the passage through vessel walls. Despite their significant role in the metastatic process, the mechanisms through which CTC clusters extravasate remain largely unknown. Based on the observed in vivo association between CTC clusters and platelets, we hypothesized that cancer cells take advantage of the platelet-derived Transforming Growth Factor Beta 1 (TGF-β1) – a signalling factor that has been widely implicated in many aspects of cancer, to facilitate their own dissemination. To address this possibility, we evaluated the effect of exogenous TGF-β1 on an experimentally evolved non-small lung cancer cell line that we previously developed and used to investigate the biology of CTC clusters. Results: We found that exogenous TGF-β1 induced the dissociation of clusters into adherent single cells. Once adhered, cells released their own TGF-β1 and were able to individually migrate and invade in the absence of exogenous TGF-β1. Based on these findings we developed a model that involves a TGF-β1-mediated plastic switch between a cooperative phenotype and a single-celled stage that enables the extravasation of CTC clusters. Conclusions: This model allows for the possibility that therapies can be developed against TGF-β1 signalling components and/or TGF-β1 target genes to suppress the metastatic potential of CTC clusters. Considering the negative impact that metastasis has on cancer prognosis and the lack of therapies against this process, interfering with the ability of CTC clusters to switch between cooperative and individual behaviours could provide new strategies to improve patient survival.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN- pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN- receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. CXCL-9,-10,-11/CXCR3 axis, dependent on IFN- signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN- pathway in the formation of brain metastasis of ER- breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

Autologous platelet-rich plasma (PRP) preparations are prepared at point of care. Centrifugation cellular density separation sequesters a fresh unit of blood into three main fractions: a platelet-poor plasma (PPP) fraction, a stratum rich in platelets (platelet concentrate) and, bioformulation dependent, also leukocyte and erythrocyte fractions. The employment of autologous platelet concentrates facilitates the biological potential to accelerate and support in numerous cellular activities that can lead to tissue repair, tissue regeneration, wound healing, and ultimately functional structural repair. Normally, after PRP preparation the PPP fraction is discarded. One of the less well known, but equally important features of PPP is that particular growth factors (GFs) are not abundantly present in PRP, as they reside outside the platelet alpha granules. Precisely, insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) are mainly present in the PPP fraction. In addition to their roles as angiogenesis activators, these plasma-based GFs are also known to inhibit inflammation, fibrosis, and they promote keratinocyte migration and support in tissue repair and wound healing. Additionally, PPP is known for the presence of exosomes and other macrovesicles, exerting cell-cell communication and cell signaling. Newly developed ultrafiltration technologies incorporate PPP processing methods by eliminating in a fast and efficient manner plasma water, cytokines, molecules, and plasma proteins with a molecular mass (weight) less than the pore size of the fibers. Consequently, a viable and viscous protein concentrate of functional, total proteins, like fibrinogen, albumin, and alpha-2-macroglobulin is created. Consolidating a small volume of high platelet concentrate with a small volume of highly concentrated protein-rich PPP creates a protein rich platelet concentrate (PRPC) biological preparation. After the activation of proteins, mainly fibrinogen, the PRPC matrix retains and facilitates interactions between invading resident cells, like macrophages, fibroblast, and mesenchymal stem cells (MSCs), and the embedded concentrated PRP cells and molecules. The administered PRPC biologic will ultimately undergo fibrinolysis, leading to a sustained release of concentrated cells and molecules that have been retained in the PRPC matrix until the matrix is dissolved. We will discuss the unique biological and tissue reparative and regenerative properties of PRPC matrix.

Our matter universe is made up of four components of dark energy (DE), dark matters (DMs), leptons and quarks which are created from the decay of the primary black hole through the inflation after big bang. In the three-dimensional quantized space model, the sum (DER) of the dark energy (DE) and radiations (R) is the flat photon space and there are 39 particles of 3 dark matters, 9 leptons and 27 quarks. Generally speaking, the mass ratio of the quarks with the 27 particles is smallest and the mass ratio of the DER photon space with the 1 massless photon is largest. Therefore, the mass ratios of DER, DMs, leptons and quarks are inversely proportional to the particle numbers of DER, DMs, leptons and quarks as the first assumption. This simple rule is called as the universe mass ratio golden rule in Fig. 12. This simple rule is successfully applied to the observed mass ratios of the Planck and WMAP missions. The best particle number combination (1, 3, 9, 27) of the four components (DER, DMs, Leptons, Quarks) to explain the Planck 2018 and WMAP results is the same as the particle number combination (1, 3, 9, 27) of the 3-dimensional quantized space model. The calculated mass ratios of DER, DMs, leptons and quarks are 67.5 %, 22.5 %, 7.5 % and 2.5 %, respectively. And the calculated mass ratios of neutrinos and ordinary matters are 5.0 % and 5.0 %, respectively. The mass ratios of the dark energy (68.47(23) %) and matters (31.53(23) %) obtained from the Planck 2018 results are consistent with the calculated mass ratios of the DER (67.5 %) and matters (32.5 %). The mass ratio of the dark energy (72.1(15) %) obtained from the WMAP 9 year results is explained as the summed mass ratio (72.5 %) of DER (67.5 %) and neutrinos (5.0 %). The universe evolution including the super-massive black holes (SMBHs) is shown in Fig. 4. The accelerated space expansion of our universe requires the addition of the new dark energy. If this new dark energy is added, the mass ratio of the dark energy is a little bit increased. The difference (0.97 %) between the observed value (68.47(23) %) and calculated value (67.5 %) is explained by adding the new dark energy in Figs. 2, 4, 7, 8, 9, 10 and 11. The corrected mass ratios of DER, DMs, leptons and quarks are 68.47 %, 21.8286 %, 7.2762 % and 2.4254 %, respectively. The corrected mass ratios of the neutrinos (called as cosmic background neutrinos) and ordinary matters (OMs) are 4.8508 % and 4.8508 %, respectively. These corrected mass ratios can explain the mass ratios obtained from the WMAP and Planck missions. In other words, the mass ratios calculated from the best particle number combination support the elementary particles, dark matters and dark energy (photon space) proposed by the three-dimensional quantized space model based on the 10-D Euclidean space.