Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1).

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

Adsorption-coupled Fenton type reduction of bromate in water by high-yield polymer-derived ceramic-supported nano-zerovalent iron.

Nano-zerovalent iron (nZVI) is a promising material for the removal of both organic and inorganic pollutants from contaminated water. This study investigates the potential of a novel composite of nZVI on a polymer-derived supporting ceramic (nZVI-PDC) synthesized via the liquid-phase reduction method for the simultaneous adsorption and Fenton-type reduction of bromate anion (BrO3-) in water. The nZVI nanoparticles were effectively anchored onto the PDC by impregnating high-yield carbon in a ferrous sulfate solution. The PDC facilitated the uniform dispersion of nZVI nanoparticles due to its multiple active sites distributed within mesocarbon cavities. The developed nZVI-PDC composite exhibited a high specific surface area of 837 m2 g-1 and an ordered mesoporous structure with a pore volume of 0.37 cm3 g-1. As an adsorbent, the nZVI-PDC composite exhibited a maximum adsorption capacity (qe) of 842 mg g-1 and a partition coefficient (KH) of 10.2 mg g-1 µM-1, as calculated by the pseudo-second-order model. As a catalyst, the composite demonstrated a reaction kinetic rate of 43.5 µmol g-1 h-1 within 6 h at pH 4, using a dosage of 60 mg L-1 nZVI-PDC and a concentration of 0.8 mmol L-1 H2O2. Comparatively, PDC exhibited a qe of 408 mg g-1, KH of 1.67 mg g-1 µM-1, and a reaction rate of 20.8 µmol g-1 h-1, while nZVI showed a qe of 456 mg g-1, KH of 2.30 mg g-1 µM-1, and a reaction rate of 27.2 µmol g-1 h-1. The modelling indicated that the nZVI-PDC composite followed pseudo-second-order kinetics. The remarkable removal efficiency of the nZVI-PDC composite was attributed to the synergistic effects between PDC and nZVI, where PDC facilitated charge transfer, promoting Fe2+ generation and the Fe3+/Fe2+ cycle. Overall, this work introduces a promising adsorption technology for the efficient removal of BrO3- from contaminated aqueous solutions, highlighting the significant potential of the nZVI-PDC composite in water purification applications.

Assessing the performance of group-based trajectory modeling method to discover different patterns of medication adherence.

It is well known that medication adherence is critical to patient outcomes and can decrease patient mortality. The Pharmacy Quality Alliance (PQA) has recognized and identified medication adherence as an important indicator of medication-use quality. Hence, there is a need to use the right methods to assess medication adherence. The PQA has endorsed the proportion of days covered (PDC) as the primary method of measuring adherence. Although easy to calculate, the PDC has however several drawbacks as a method of measuring adherence. PDC is a deterministic approach that cannot capture the complexity of a dynamic phenomenon. Group-based trajectory modeling (GBTM) is increasingly proposed as an alternative to capture heterogeneity in medication adherence. The main goal of this paper is to demonstrate, through a simulation study, the ability of GBTM to capture treatment adherence when compared to its deterministic PDC analogue and to the nonparametric longitudinal K-means. A time-varying treatment was generated as a quadratic function of time, baseline, and time-varying covariates. Three trajectory models are considered combining a cat's cradle effect, and a rainbow effect. The performance of GBTM was compared to the PDC and longitudinal K-means using the absolute bias, the variance, the c-statistics, the relative bias, and the relative variance. For all explored scenarios, we find that GBTM performed better in capturing different patterns of medication adherence with lower relative bias and variance even under model misspecification than PDC and longitudinal K-means.

Breakthrough in Blastic Plasmacytoid Dendritic Cell Neoplasm Cancer Therapy Owing to Precision Targeting of CD123.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic cancer originating from the malignant transformation of plasmacytoid dendritic cell precursors. This malignancy progresses rapidly, with frequent relapses and a poor overall survival rate, underscoring the urgent need for effective treatments. However, diagnosing and treating BPDCN have historically been challenging due to its rarity and the lack of standardized approaches. The recognition of BPDCN as a distinct disease entity is recent, and standardized treatment protocols are yet to be established. Traditionally, conventional chemotherapy and stem cell transplantation have been the primary methods for treating BPDCN patients. Advances in immunophenotyping and molecular profiling have identified potential therapeutic targets, leading to a shift toward CD123-targeted immunotherapies in both clinical and research settings. Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. However, the therapeutic effectiveness of CD123-targeting treatments needs improvement through innovative approaches and combinations of treatments with other anti-leukemic drugs. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

Innovative prognostic modeling in ESCC: leveraging scRNA-seq and bulk-RNA for dendritic cell heterogeneity analysis.

Background: Globally, esophageal squamous cell carcinoma (ESCC) stands out as a common cancer type, characterized by its notably high rates of occurrence and mortality. Recent advancements in treatment methods, including immunotherapy, have shown promise, yet the prognosis remains poor. In the context of tumor development and treatment outcomes, the tumor microenvironment (TME), especially the function of dendritic cells (DCs), is significantly influential. Our study aims to delve deeper into the heterogeneity of DCs in ESCC using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis. Methods: In the scRNA-seq analysis, we utilized the SCP package for result visualization and functional enrichment analysis of cell subpopulations. CellChat was employed to identify potential oncogenic mechanisms in DCs, while Monocle 2 traced the evolutionary trajectory of the three DC subtypes. CopyKAT assessed the benign or malignant nature of cells, and SCENIC conducted transcription factor regulatory network analysis, offering a preliminary exploration of DC heterogeneity. In Bulk-RNA analysis, we constructed a prognostic model for ESCC prognosis and immunotherapy response, based on DC marker genes. This model was validated through quantitative PCR (qPCR) and immunohistochemistry (IHC), confirming the gene expression levels. Results: In this study, through intercellular communication analysis, we identified GALECTIN and MHC-I signaling pathways as potential oncogenic mechanisms within dendritic cells. We categorized DCs into three subtypes: plasmacytoid (pDC), conventional (cDC), and tolerogenic (tDC). Our findings revealed that pDCs exhibited an increased proportion of cells in the G2/M and S phases, indicating enhanced cellular activity. Pseudotime trajectory analysis demonstrated that cDCs were in early stages of differentiation, whereas tDCs were in more advanced stages, with pDCs distributed across both early and late differentiation phases. Prognostic analysis highlighted a significant correlation between pDCs and tDCs with the prognosis of ESCC (P< 0.05), while no significant correlation was observed between cDCs and ESCC prognosis (P = 0.31). The analysis of cell malignancy showed the lowest proportion of malignant cells in cDCs (17%), followed by pDCs (29%), and the highest in tDCs (48%), with these results being statistically significant (P< 0.05). We developed a robust ESCC prognostic model based on marker genes of pDCs and tDCs in the GSE53624 cohort (n = 119), which was validated in the TCGA-ESCC cohort (n = 139) and the IMvigor210 immunotherapy cohort (n = 298) (P< 0.05). Additionally, we supplemented the study with a novel nomogram that integrates clinical features and risk assessments. Finally, the expression levels of genes involved in the model were validated using qPCR (n = 8) and IHC (n = 16), thereby confirming the accuracy of our analysis. Conclusion: This study enhances the understanding of dendritic cell heterogeneity in ESCC and its impact on patient prognosis. The insights gained from scRNA-seq and Bulk-RNA analysis contribute to the development of novel biomarkers and therapeutic targets. Our prognostic models based on DC-related gene signatures hold promise for improving ESCC patient stratification and guiding treatment decisions.

Role of plasmacytoid dendritic cells in vascular dysfunction in mice with renovascular hypertension.

Endothelial dysfunction and inflammation are clinically significant risk factors for cardiovascular diseases in hypertension. Although immune cells play a role in hypertension, the impact of plasmacytoid dendritic cells in established renovascular hypertension-induced cardiovascular complications is not fully understood. We investigated plasmacytoid dendritic cells' contribution to arterial endothelial dysfunction and inflammation in renovascular hypertension. A two-kidney one-clip (2K1C) model for four weeks in both male and female mice was used to induce renovascular hypertension. We treated mice with or without anti-PDCA-1 antibodies for one week to deplete the plasmacytoid dendritic cells. Renovascular hypertension causes cardiac hypertrophy, lung edema, and microvascular endothelial dysfunction associated with inflammation induction in mice. Moreover, renovascular hypertension affects the profile of immune cells, including dendritic cells and macrophages, with variations between male and female mice. Interestingly, the depletion of plasmacytoid dendritic cells significantly reduces blood pressure, cardiac hypertrophy, lung edema, inflammation, and oxidative stress and improves microvascular endothelial function via the endoplasmic reticulum (ER) stress, autophagy, and mTOR-dependent mechanisms. Plasmacytoid dendritic cells significantly contribute to the development of cardiovascular complications in renovascular hypertension by modulating immune cells, inflammation, oxidative stress, and ER stress.

LC-MS/MS method for dual-ligand peptide-drug CBP-1018 and its deconjugated payload MMAE including sample stabilization strategy for its MC-Val-Cit-PABC linker.

Recently, peptide-drug conjugate (PDC) has become the most promising conjugated drug for tumor therapy after antibody-drug conjugate due to stronger tumor penetration capacity and lower immunogenicity. CBP-1018 was a PDC with dual-ligand conjugated to MMAE via a cleavable linker (MC-Val-Cit-PABC) that can be lysed by cathepsins B. In this study, two specific LC-MS/MS methods were developed and validated for the determination of CBP-1018 and its metabolite MMAE in human plasma. To prevent the cleavable MC-Val-Cit-PABC linker from degradation, a protease inhibitor (cOmplete solution) was added to the pre-cooled vacuum tubes and the separated plasma samples. The assays involved the pretreatment of CBP-1018 by protein precipitation with H2O-ACN (1:9, v/v) and the extraction of MMAE by liquid-liquid extraction with ethyl acetate under alkaline condition to eliminate the interference of CBP-1018 on MMAE. The two analytes showed good linearities over the calibration ranges (R2 ≥ 9980). Both accuracy and precision met the acceptance criteria. The validated methods were successfully applied to the phase I dose-escalation study of CBP-1018 injection in Chinese patients with solid tumors to evaluate the pharmacokinetic properties of CBP-1018 and MMAE. The results showed that CBP-1018 was eliminated immediately after injection and MMAE reached the maximum exposure at approximately 2 h after infusion. The maximum concentration of MMAE did not exceed 20.0 ng/mL, suggesting that the off-target toxicity of CBP-1018 injection was controllable.

Development of a rock-bit interaction analytical model by considering the in-situ stresses for a bottom-hole element.

PDC drill bits are an important part of drilling engineering, but improper selection or design can lead to decreased performance and increased costs. Then, accurate modeling of rock-bit interaction for Oil/gas well drilling is critical. Although several mathematical models are presented for this purpose, they have not been able to present a comprehensive model for the rock-bit interaction. In-situ stresses in real drilling conditions affect the force required for rock failure. However, the models proposed so far either have not considered the effects of in-situ stresses or have assumed that the rock failure angle in the downhole conditions is equal to the one calculated in the atmospheric conditions. In this work, after reviewing the background of studies conducted on the rock and bit interaction, with an analytical method, stresses applied to the bottom hole element are examined, including stresses resulting from bit and in-situ stresses. Based on the principle of superposition, the total stress imposed on the bottom hole element is calculated to determine the angle and force of rock cutting. Finally, a novel mathematical model of rock-bit interaction in vertical and deviated oil/gas wells drilling by Considering In-Situ Stresses is presented. Also, the study compares the current model to the Nishimatsu and Xin Ling models using data from a southwest field in Iran. The results show that the simplifying assumption made by previous models leads to a significant underestimation of the failure angle and the amount of force required to the rock failure, with reductions of up to 21% and 48%, respectively, in the case of a vertical well. In an inclined well, the current model predicts cutting force at about 0.14 of that predicted by the previous model.

How to Administer the Performance Diagnostic Checklist-Human Services.

The Performance Diagnostic Checklist-Human Services (PDC-HS) is a performance analysis tool used to identify barriers to performance in human-service settings. Multiple published studies have used the PDC-HS to determine effective interventions (Wilder et al. Journal of Applied Behavior Analysis 53(2), 1170-1176, 2020). However, in a recent discussion article proposing guidelines for administering the PDC-HS, Brand et al. Behavior Analysis in Practice, 1-7 (2022) noted that procedural descriptions provided for administering the PDC-HS are somewhat ambiguous in the published literature. The purpose of the current systematic review was to compare methods used to administer the PDC-HS. Fifteen articles met inclusion criteria and were coded to evaluate commonalities among PDC-HS components. Authors generally agreed on how the outcomes of the PDC-HS were depicted and discussed but varied in their descriptions of methods used to administer the PDC-HS. Results are discussed in terms of the importance of technological descriptions and directions for future research towards the development of a more standardized tool. Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-023-00848-3.

Prediction of formation abrasiveness under the action of a PDC bit based on the fractal dimension of a rock surface.

During rock drilling, a drill bit will wear as it breaks the rock. However, there is no uniform grading standard for rock abrasiveness. To solve this problem, the wear mechanisms of a polycrystalline diamond compact (PDC) bit and the formation it is drilling into are analyzed in depth, and an abrasiveness evaluation method based on the fractal dimension of the rock surface topography is established. Initially, a three-dimensional digital model is generated from a scanning electron microscope image of the rock after drilling; next, an evaluation of the irregularities on the rock surface is performed using an adapted Weierstrass-Mandelbrot (W-M) function to ascertain the fractal dimensionality. Then, the microcontact characteristics of the contact surface between the formation and the PDC bit are analyzed, and the distribution of the microconvex contact points of the two-body friction pair in a region is obtained. Because the sliding friction between the drill bit and the rock produces a large amount of heat, according to the contact area formula of the friction surface and heat conduction theory, the temperature rise and overall temperature distribution of the formation and PDC bit under the condition of sliding friction are revealed, and the real contact area between the formation and the drill bit within a certain temperature range is obtained. Finally, the evaluation index of rock abrasiveness under sliding conditions is established by adopting the wear weight loss of the rock cutting tool per unit volume as the index of rock abrasiveness, and the model is verified by a microdrilling experiment. The research in this paper is highly important for improving the rock-breaking efficiency and bit service life during drilling.

Peptide Therapeutics: Unveiling the Potential against Cancer-A Journey through 1989.

The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody-drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects.

Structural Design and Analysis of Large-Diameter D30 Conical Polycrystal Diamond Compact (PDC) Teeth under Engineering Rotary Mining Conditions.

In the realm of engineering rotary excavation, the rigid and brittle nature of the Polycrystal Diamond Compact (PDC) layer poses challenges to the impact resistance of conical teeth. This hinders their widespread adoption and utilization. In this paper, the Abaqus simulation is used. By optimizing the parameters of the radius of the cone top arc, we analyzed the changing law of the parameters of large-diameter D30 series conical PDC teeth, such as the equivalent force, impact force, and energy absorption of the conical teeth during the impact process, and optimized the best structure of the conical PDC teeth. After being subjected to a high temperature and high pressure, we synthesized the specimen for impact testing and analyzed the PDC layer crack extension and fracture failure. The findings reveal the emergence of a stress ring below the compacted area of the conical tooth. As the radius of the cone top arc increases, so does the area of the stress ring. When R ≥ 10 mm, the maximum stress change is minimal, and at R = 10 mm, the stress change in its top unit is relatively smooth. Optimal impact resistance is achieved, withstanding a total impact work value of 7500 J. Extrusion cracks appear in the combined layer part of PDC layers I and II, but the crack source is easy to produce in the combined layer of PDC layer II and the alloy matrix and extends to both sides, and the right side extends to the surface of the conical tooth in a "dragon-claw". The failure morphology of the conical teeth includes ring shedding at the top of the PDC layer, the lateral spalling of the PDC layer, and the overall cracking of the conical teeth. Through this study, we aim to promote the popularization and application of large-diameter conical PDC teeth in the field of engineering rotary excavation.

Digging in real-word electronic database for assessing CDK 4/6 inhibitors adherence in breast cancer patients from Romania.

Introduction: It is imperative for patients to respect the prescribed treatments to achieve the anticipated clinical outcomes, including the outpatients receiving oral anti-cancer drugs such as selective cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). With the introduction of three CDK 4/6i drugs in the Romanian pharmaceutical market in 2018, our study aimed to evaluate medication adherence and the influencing factors among patients undergoing treatment with palbociclib, ribociclib, or abemaciclib for advanced or metastatic breast cancer. Methods: Medication adherence was assessed using the Proportion of Days Covered (PDC) method, and Spearman correlation analysis was conducted to explore the relationships between adherence, age, gender, and follow-up duration. Results: The study enrolled 330 breast cancer patients, with an average follow-up period of 14.6 ± 12.5 months for palbociclib, 10.6 ± 7.1 months for ribociclib, and 8.6 ± 6.4 months for abemaciclib-treated patients. A small proportion of patients demonstrated non-adherence: 12.8% for palbociclib, 14.6% for ribociclib, and 14.7% for abemaciclib. Among patients receiving palbociclib, there was no significant correlation between adherence, age (rho = 0.07, p = 0.35), or gender (rho = -0.144, p = 0.054). However, a significant correlation was found with the duration of follow-up (rho = -0.304, p < 0.0001). Similar results were observed for patients receiving ribociclib or abemaciclib. Most patients received combination therapy with letrozole (46%) and exemestane (13%) for palbociclib, letrozole (48%) and fulvestrant (19%) for ribociclib, and fulvestrant (39%) and letrozole (27%) for abemaciclib, Discussion: High adherence rates were observed among patients treated with CDK 4/6i drugs, with no significant differences noted among the three drugs in this class. However, the collected patient data was limited, lacking information on adverse reactions that could potentially lead to treatment discontinuation, as determined by the oncologist's decision not to prescribe. Consequently, a comprehensive understanding of all factors contributing to the low adherence levels is hindered.

Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer.

Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an "innate checkpoint", reminiscent of the function of "classical" adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy.

Association between the traditional Chinese medicine constitution and metabolic dysfunction-associated fatty liver disease in older people: A cross-sectional study.

Background: Few studies have focused on the relationship between the traditional Chinese medicine constitution (TCMC) and metabolic dysfunction-associated fatty liver disease (MAFLD) in older populations. We sought to investigate the distribution of MAFLD and the TCMC in older people, and provide a theoretical basis for TCMC-based management of MAFLD in this population. Methods: A cross-sectional study was conducted among older (≥65 years) individuals in Zhongshan, China. Information on common sociodemographic characteristics, medical history, anthropometric measurements, and the TCMC was collected. The chi-square test, multivariable logistic regression analysis, subgroup analysis, and inverse probability weighting of the propensity score were used to explore the relationship between MAFLD and the TCMC. Results: Of 7085 participants, 1408 (19.9 %) had MAFLD. The three most common TCMC types in MAFLD patients were "phlegm-dampness", "gentleness", and "yin-deficiency". After adjustment for gender, age, tobacco smoking, alcohol consumption, body mass index, abnormal waist-to-hip ratio, hypertension, diabetes mellitus, and dyslipidemia, MAFLD was positively associated with the phlegm-dampness constitution (PDC) (ORadjusted (95 % CI) = 1.776 (1.496-2.108), P < 0.001), and negatively correlated with the qi-depression constitution (0.643 (0.481-0.860), 0.003). A stronger correlation between the PDC and MAFLD was observed in men compared with women (ORadjusted = 2.04 (95%CI = 1.47-2.84) vs. 1.70 (95%CI = 1.39-2.08), Pinteraction = 0.003) as well as between people who smoked tobacco and non-tobacco-smoking individuals (2.11 (1.39-3.21) vs. 1.75 (1.45-2.12), 0.006). Conclusions: A positive relationship was observed between MAFLD and the PDC in older people living in Zhongshan. Early detection and treatment of the PDC (especially in men and smokers) could prevent the occurrence and development of MAFLD.

Role of a National Health Service Electronic Prescriptions Database in the Detection of Prescribing and Dispensing Issues and Adherence Evaluation of Direct Oral Anticoagulants.

BACKGROUND: Anticoagulation therapy plays a crucial role in the management of atrial fibrillation (AF) by significantly reducing the risk of stroke. Direct oral anticoagulants (DOAC) became preferred over warfarin due to their superior safety and efficacy profile. Assessing adherence to anticoagulation therapy is necessary in clinical practice for optimising patient outcomes and treatment efficacy, thus emphasising its significance. METHODS: A retrospective study utilised the Latvian National Health Service reimbursement prescriptions database, covering prescriptions for AF and flutter from January 2012 to December 2022. The proportion of days covered method was selected for adherence assessment, categorising it into three groups: (1) below 80%, (2) between 80% and 90%, and (3) above 90%. RESULTS: A total of 1,646,648 prescriptions were analysed. Dabigatran prescriptions started declining after 2020, coinciding with a decrease in warfarin prescriptions since 2018. The total adherence levels to DOAC therapy were 69.4%. Only 44.2% of users achieved an adherence level exceeding 80%. The rate of paper prescriptions decreased from 98.5% in 2017 to 1.3% in 2022. Additionally, the utilisation of international non-proprietary names reached 79.7% in 2022. Specifically, 16.7% of patients selected a single pharmacy, whereas 27.7% visited one or two pharmacies. Meanwhile, other patients obtained medicines from multiple pharmacies. CONCLUSIONS: The total adherence level to DOAC therapy is evaluated as low and there was no significant difference in age, gender, or "switcher" status among adherence groups. Physicians' prescribing habits have changed over a decade.

TDP-43 and Alzheimer's Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA.

Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer's disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called ß-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-ß plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk.

Identification of macaque dendritic cell precursors in blood and tissue reveals their dysregulation in early SIV infection.

Distinct dendritic cell (DC) subsets play important roles in shaping immune responses. Circulating DC precursors (pre-DCs) are more susceptible to HIV infection in vitro, which may explain the inefficiency of immune responses against HIV. However, the interplay between HIV and pre-DC is not defined in vivo. We identify human pre-DC equivalents in the cynomolgus macaque and then analyze their dynamics during simian immunodeficiency virus (SIV) infection to illustrate a sharp decrease of blood pre-DCs in early SIV infection and accumulation in lymph nodes (LNs), where they neglect to upregulate CD83/CD86 or MHC-II. Additionally, SIV infection attenuates the capacity of stimulated LN pre-DCs to produce IL-12p40. Analysis of HIV cohorts provides correlation between costimulatory molecule expression on pre-DCs and T cell activation in spontaneous HIV controllers. These findings pinpoint certain dynamics and functional changes of pre-DCs during SIV infection, providing a deeper understanding of immune dysregulation mechanisms elicited in people living with HIV.