Search

JAK-STAT signaling cascade has emerged as an ideal target for the treatment of myeloproliferative diseases, autoimmune diseases, and neurological disorders. Ruxolitinib (Rux), is an orally bioavailable, potent and selective Janus-associated kinase (JAK) inhibitor, proven to be effective to target activated JAK-STAT pathway in the diseases previously described. Unfortunately, limited studies have investigated the potential cytotoxic profile of Rux on other cell populations within the heterogenous CNS microenvironment. Two stem and progenitor cell populations, namely the oligodendrocyte precursor cells (OPCs) and neural stem/progenitor cells (NSPCs), are important for long-term maintenance and post-injury recovery response of the CNS. In light of the limited evidence, this study sought to investigate further the effect of Rux on proliferating and differentiating OPCs and NSPCs populations. In the present study, cultured rat OPCs and NSPCs were treated with various concentrations of Rux, ranging from 2 μM to 20 μM. The effect of Rux on proliferating OPCs (PDGF-R-α+) and proliferating NSPCs (nestin+) was assessed via a 3-day Rux treatment, whereas its effect on differentiating OPCs (MBP+/PDGF-R-α+) and differentiating NSPCs (neurofilament+) was assessed after a 7-day treatment. Cytotoxicity of Rux was also assessed on OPC populations by examining its influence on cell death and DNA synthesis via YO-PRO-1/PI dual-staining and BrdU assay, respectively. The results suggest that Rux at a dosage above 10 μM reduces the number proliferating OPCs, likely via the induction of apoptosis. On the other hand, Rux treatment from 2.5 μM to 20 μM significantly reduces the number of differentiating OPCs by inducing necrosis. Meanwhile, Rux treatment has no observable untoward impact on NSPC cultures within the dosage range tested. Taken together, OPCs appears to be more vulnerable to the dosage effect of Rux, whereas NSPCs are not significantly impacted by Rux, suggesting a differential mechanism of actions of Rux on the cell types.

Graphical abstract:

Calls for more diverse data in genetics studies typically fall short of offering further guidance. Here we summarize a policy framework from the Global Alliance for Genomics and Health designed to fill this gap. The framework prompts researchers to consider both what types of diversity are needed and why, and how aims can be achieved through choices made throughout the data life cycle.

Purpose: Hostile aortic neck characteristics, including short length, severe suprarenal and infrarenal angulation, conicity, and large diameter, have been associated with increased risk for type Ia endoleak (T1aEL) after endovascular aneurysm repair (EVAR). This study investigates the mid-term discriminative ability of a statistical shape model (SSM) of the infrarenal aortic neck morphology compared with or in combination with conventional measurements in patients who developed T1aEL post-EVAR.Materials and Methods: The dataset composed of EVAR patients who developed a T1aEL during follow-up and a control group without T1aEL. Principal component (PC) analysis was performed using a parametrization to create an SSM. Three logistic regression models were created. To discriminate between patients with and without T1aEL, sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were calculated.Results: In total, 126 patients (84% male) were included. Median follow-up time in T1aEl group and control group was 52 (31, 78.5) and 51 (40, 62.5) months, respectively. Median follow-up time was not statistically different between the groups (p=0.72). A statistically significant difference between the median PC scores of the T1aEL and control groups was found for the first, eighth, and ninth PC. Sensitivity, specificity, and AUC values for the SSM-based versus the conventional measurements–based logistic regression models were 79%, 70%, and 0.82 versus 74%, 73%, and 0.85, respectively. The model of the SSM and conventional measurements combined resulted in sensitivity, specificity, and AUC of 81%, 81%, and 0.92.Conclusion: An SSM of the infrarenal aortic neck determines its 3-dimensional geometry. The SSM is a potential valuable tool for risk stratification and T1aEL prediction in EVAR. The SSM complements the conventional measurements of the individual preoperative infrarenal aortic neck geometry by increasing the predictive value for late type Ia endoleak after standard EVAR.Clinical Impact A statistical shape model (SSM) determines the 3-dimensional geometry of the infrarenal aortic neck. The SSM complements the conventional measurements of the individual pre-operative infrarenal aortic neck geometry by increasing the predictive value for late type Ia endoleaks post-EVAR. The SSM is a potential valuable tool for risk stratification and late T1aEL prediction in EVAR and it is a first step toward implementation of a treatment planning support tool in daily clinical practice.

This study investigates the synthesis and optimization of nanobots (NBs) loaded with pDNA using the layer-by-layer (LBL) method and explores the impact of their collective motion on the transfection efficiency. NBs consist of biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and are powered by the urease enzyme, enabling autonomous movement and collective swarming behavior. In vitroexperiments were conducted to validate the delivery efficiency of fluorescently labeled NBs, using two-dimensional (2D) and three-dimensional (3D) cell models: murine urothelial carcinoma cell line (MB49) and spheroids from human urothelial bladder cancer cells (RT4). Swarms of pDNA-loaded NBs showed enhancements of 2.2- to 2.6-fold in delivery efficiency and 6.8- to 8.1-fold in material delivered compared to inhibited particles (inhibited enzyme) and the absence of fuel in a 2D cell culture. Additionally, efficient intracellular delivery of pDNA was demonstrated in both cell models by quantifying and visualizing the expression of eGFP. Swarms of NBs exhibited a >5-fold enhancement in transfection efficiency compared to the absence of fuel in a 2D culture, even surpassing the Lipofectamine 3000 commercial transfection agent (cationic lipid-mediated transfection). Swarms also demonstrated up to a 3.2-fold enhancement in the amount of material delivered in 3D spheroids compared to the absence of fuel. The successful transfection of 2D and 3D cell cultures using swarms of LBL PLGA NBs holds great potential for nucleic acid delivery in the context of bladder treatments.

Background: Huntington’s disease (HD) presents patients and individuals at risk for HD with significant levels of stress. However, relatively little research has examined how individuals cope with stress related to the disease or the association of specific coping strategies with psychological symptoms.Objective: This study examined the ways in which HD patients and at-risk individuals cope with HD-related stress using a control-based model of coping and the association of coping strategies with symptoms of depression and anxiety.Methods: HD patients (n= 49) and at-risk individuals (n= 76) completed the Responses to Stress Questionnaire – Huntington’s Disease Version to assess coping strategies in response to HD-related stress, as well as standardized measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics.Results: Patients and at-risk individuals reported using comparable levels of primary control coping, secondary control coping, and disengagement coping strategies. In linear regression analyses, only secondary control coping was significantly associated with lower depression (β= –0.62, p< 0.001) and anxiety (β= –0.59, p< 0.001) symptoms in patients and at-risk individuals (β= –0.55, p< 0.001 and β= –0.50, p< 0.001, respectively).Conclusions: Secondary control coping may be beneficial for both HD patients and at-risk individuals. Future research using the control-based model of coping in longitudinal studies with the HD population is needed, and future interventions could test the effects of cognitive reframing and acceptance as coping strategies for families affected by HD.

ABSTRACT:Henry Clay Lewis's "Valerian and the Panther" (1850) offers a rich source for thinking about the haunting discourses of animals, extinction, and human geographies in the Anthropocene channeled through the focus on North America's infamous panther. The panther has become immortalized within the culture of the US South through both its significant role within the history of North America as well as its subsequent mythological construction as the American "ghost cat." Lewis's shadowy panther traverses the boundaries between life and death, between past and present, to haunt the swamp as the shadowy "ghost cat"—an effectively extinct animal whose continued place within the literary landscape is maintained by its spectral mythologization. Ultimately, this article argues that Lewis's panther materializes as a ghostly omen of the ecological destruction wrought by settler colonialism and a testament to the consequences of this destruction felt in our present moment through the large-scale extinction and notable absence of key species.

We built a reference panel with 342 million autosomal variants using 78,195 individuals from the Genomics England (GEL) dataset, achieving a phasing switch error rate of 0.18% for European samples and imputation quality of r2= 0.75 for variants with minor allele frequencies as low as 2 × 10−4in white British samples. The GEL-imputed UK Biobank genome-wide association analysis identified 70% of associations found by direct exome sequencing (P< 2.18 × 10−11), while extending testing of rare variants to the entire genome. Coding variants dominated the rare-variant genome-wide association results, implying less disruptive effects of rare non-coding variants.

Several conjugates between folic acid and a series of kinetically stable lanthanide complexes have been synthesized, using amide coupling and azide–alkyne cycloaddition methodologies to link the metal-binding domain to folate through a variety of spacer groups. While all these complexes exhibit affinity for the folate receptor, it is clear that the point of attachment to folate is essential, with linkage through the γ-carboxylic acid giving rise to significantly enhanced receptor affinity. All the conjugates studied show affinities consistent with displacing biological circulating folate derivatives, 5-methyltetrahydrofolate, from folate receptors. All the complexes exhibit luminescence with a short-lived component arising from ligand fluorescence overlaid on a much longer lived terbium-centered component. These can be separated using time-gating methods. From the results obtained, the most promising approach to achieve sensitized luminescence in these systems requires incorporating a sensitizing chromophore close to the lanthanide.

Biological barriers present a significant obstacle to treatment, especially when drugs are administered locally to increase their concentrations at the target site while minimizing unintended off-target effects. Among these barriers, mucus presents a challenge, as it serves as a protective layer in the respiratory, urogenital, and gastrointestinal tracts. Its role is to shield the underlying epithelial cells from pathogens and toxic compounds but also impedes the efficient delivery of drugs. Despite the exploration of mucolytic agents to improve drug delivery, overcoming this protective barrier remains a significant hurdle. In our study, we investigate an alternative approach involving the use of catalase-powered nanobots. We use an in vitromodel that simulates intestinal mucus secretion to demonstrate the dual functionality of our nanobots. This includes their ability to disrupt mucus, which we confirmed through in vitroand ex vivovalidation, as well as their self-propulsion to overcome the mucus barrier, resulting in a 60-fold increase compared with passive nanoparticles. Therefore, our findings highlight the potential utility of catalase-powered nanobots as carriers for therapeutic agents since they could enhance drug delivery efficiency by penetrating the mucus barrier.

Objective:The objective of this study was to evaluate whether a systematic image assessment protocol using SPY Elite images (LifeCell Corp., US) of viable tissue at the periphery of the surgical field was associated with positive wound healing outcomes following mastectomy and breast reconstruction.Method:Patients undergoing mastectomy and subsequent breast reconstruction surgery at a single tertiary medical centre were included. SPY images were prospectively analysed using a systematic image assessment protocol, and an absolute value of mean fluorescence was calculated by measuring peripheral, in-situ tissue from each image. Patient medical records were retrospectively reviewed for demographics, surgical characteristics and postoperative outcomes. These variables were statistically tested for associations with mean fluorescence.Results:A total of 63 patients were included in the final analysis. We found that objectively determined mean fluorescence values were not statistically significantly associated with postoperative complications.Conclusion:In this study, objectively measured mean fluorescence values representing breast tissue remaining after dissection showed little utility in the assessment of postoperative wound healing outcomes as they did not identify patients who would later have complications of wound healing.Declaration of interest:The authors have no conflicts of interest to declare.

Carotenoids are fat-soluble phytochemicals with biological roles, including ultraviolet protective functions in skin. Spectroscopic skin carotenoid measurements can also serve as a noninvasive biomarker for carotenoid consumption. Single-nucleotide polymorphisms (SNPs) in metabolic genes are associated with human plasma carotenoid concentrations; however, their relationships with skin carotenoid concentrations are unknown.