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A key hallmark of Parkinson’s disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with α-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril α-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans. The impact of α-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of α-synucleinopathy.

The development of secure romantic relationships is an important developmental task for many emerging adults. Emerging adults who report more secure romantic attachments also report greater overall life satisfaction. The goal of the current study was to identify family-of-origin predictors of romantic attachment styles among emerging adults. College students ( n  = 288) completed measures of parental psychological control, early maladaptive schemas, and anxious and avoidant romantic attachment. Findings supported a theoretical mediation model where parental psychological control was related to higher rates of anxious and avoidant romantic attachment, and this relationship was mediated by early maladaptive schemas. These findings indicate the importance of considering family-of-origin patterns when examining romantic attachment in emerging adults. Therapists and other helpers may be better able to support the development of secure romantic attachment by also addressing maladaptive schemas that may impact romantic relationship development.

Recurrent gain-of-function mutations in the histone reader protein ENL have been identified in Wilms tumor, the most prevalent pediatric kidney cancer. However, their pathological significance in kidney development and tumorigenesis in vivo remains elusive. Here, we generate mouse models mimicking ENL tumor (ENL T ) mutations and show that heterozygous mutant expression in Six2 + nephrogenic or Foxd1 + stromal lineages leads to severe, lineage-specific kidney defects, both resulting in neonatal lethality. Six2-ENL T mutant kidneys display compromised cap mesenchyme, scant nephron tubules, and cystic glomeruli, indicative of premature progenitor commitment and blocked differentiation. Bulk and spatial transcriptomic analyses reveal aberrant activation of Hox and Wnt signaling genes in mutant nephrogenic cells. In contrast, Foxd1-ENL T mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, with dysregulated stromal gene expression affecting stroma-epithelium crosstalk. Our findings uncover distinct pathways through which ENL mutations disrupt nephrogenesis, providing a foundation for further investigations into their role in tumorigenesis. The histone reader ENL is frequently mutated in Wilms tumor. Here they use mouse models and spatial transcriptomic analyses to show how ENL tumor mutations disrupt nephrogenesis through distinct pathways in nephrogenic and stromal lineages.

Parkinson’s Disease (PD) is the second most common neurodegenerative disease worldwide, affecting 1 % of the population over 65 years of age. Dopaminergic cell death in the substantia nigra and accumulation of Lewy bodies are the defining neuropathological hallmarks of the disease. Neuronal death and dysfunction have been reported in other central nervous system regions, including the retina. Symptoms of PD typically manifest only when more than 70 % of dopaminergic cells are lost, and the definitive diagnosis of PD can only be made histologically at post-mortem, with few biomarkers available. In this study, a rotenone-induced rodent model of PD was employed to investigate retinal manifestations in PD and their usefulness in assessing the efficacy of a novel therapeutic intervention with a liposomal formulation of the PPAR-γ (Peroxisome proliferator-activated receptor gamma) agonist rosiglitazone. Retinal assessment was performed using longitudinal in vivo imaging with DARC (detection of apoptosing retinal cells) and OCT (optical coherence tomography) technologies and revealed increased RGCs (Retinal Ganglion Cells) apoptosis and a transient swelling of the retinal layers at day 20 of the rotenone insult. Follow-up of this model demonstrated characteristic histological neurodegenerative changes in the substantia nigra and striatum by day 60, suggesting that retinal changes precede the “traditional” pathological manifestations of PD. The therapeutic effect of systemic administration of different formulations of rosiglitazone was then evaluated, both in the retina and the brain. Of all treatment regimen tested, sustained release administration of liposome-encapsulated rosiglitazone proved to be the most potent therapeutic strategy, as evidenced by its significant neuroprotective effect on retinal neurons at day 20, and on nigrostriatal neurons at day 60, provided convincing evidence for its potential as a treatment for PD. Our results demonstrate significant retinal changes occurring in this model of PD. We show that rosiglitazone can efficiently protect retinal neurons from the rotenone insult, and that systemic administration of liposome-encapsulated rosiglitazone has an enhanced neuroprotective effect on the retina and CNS (Central Nervous System). To our knowledge, this is the first in vivo evidence of RGCs loss and early retinal thickness alterations in a PD model. Together, these findings suggest that retinal changes may be a good surrogate biomarker for PD, which may be used to assess new treatments both experimentally and clinically.

The amyloid beta (A β ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer’s disease and more recently, glaucoma. Here, we identify the α 2 adrenergic receptor agonists ( α 2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic A β -pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α 2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α 2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P <0.01) and 98% and 92.3% (Clo, P <0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental A β -induced neurotoxicity model (67% BMD and 88.6% Clo, both P <0.01, respectively), and in vitro , where α 2ARAs significantly ( P <0.05) prevented cell death, under both hypoxic (CoCl 2 ) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in A β and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and in vitro with all three α 2ARAs. BMD significantly increased soluble APP α (sAPP α ) levels at 3 and 8 weeks (2.1 and 1.6-fold) in vivo and in vitro with the CoCl 2 and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPP α antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that α 2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in A β through APP processing. Together, these results provide new evidence that α 2ARAs are neuroprotective through their effects on the A β pathway and sAPP α , which to our knowledge, is the first description. Studies have identified the need for α -secretase activators and sAPP α -mimetics in neurodegeneration; α 2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving A β .

Background Peripherally inserted central catheters (PICCs) are common vascular access devices inserted for adults undergoing intravenous treatment in the community setting. Individuals with a PICC report challenges understanding information and adapting to the device both practically and psychologically at home. There is a lack of research investigating the supportive care needs of individuals with a PICC to inform nursing assessment and the provision of additional supports they may require to successfully adapt to life with a PICC. The aim of this study was to identify the supportive care needs of adults with cancer or infection living with a PICC at home. Method Qualitative, semi-structured interviews were used to identify supportive care needs of adults living with a PICC at home. Participants were recruited from cancer and infectious diseases outpatient units. Two researchers independently analysed transcripts using content analysis. Results A total of 15 participants were interviewed (30–87 years old). There were 5 males and 10 females interviewed, 9 participants had a cancer diagnosis and most lived in a metropolitan area. Many participants lived with a partner/spouse at home and three participants had young children. Participants identified supportive care needs in the following eight categories (i (i) Adapting daily life (ii) Physical comfort (iii) Self-management (iv) Emotional impact (v) Information content (vi) Understanding information (vii) Healthcare resources and (viii) Social supports. Conclusions Adults living with a PICC at home report a broad range of supportive care needs. In addition to practical and information needs, health consumers may also require support to accept living with a device inside their body and to assume responsibility for the PICC. These findings may provide nurses with a greater understanding of individual needs and guide the provision of appropriate supports.

This study examined the efficacy of a brief (four session) intimate partner violence (IPV) prevention program ( Building a Lasting Love , Langhinrichsen-Rohling et al. 2005 ) that was designed to reduce the relationship violence of predominantly African American inner-city adolescent girls ( n  = 72) who were receiving teen pregnancy services. These high-risk girls were randomly assigned to the prevention program ( n  = 39) or waitlist control ( n  = 33) conditions. Implementation fidelity was documented. As predicted, girls who successfully completed the program ( n  = 24) reported significant reductions in their perpetration of psychological abuse toward their baby’s father as compared to the control ( n  = 23) participants. They also reported experiencing significantly less severe IPV victimization over the course of the program. Preliminary analyses indicated that avoidant attachment to one’s partner may be associated with less program-related change. These findings support the contention that brief IPV prevention programs can be targeted to selected groups of high-risk adolescents.

Glaucoma is one of the leading causes of blindness in developed countries and is mainly attributable to the apoptosis of retinal ganglion cells (RGCs). Although several diagnostic tools have been developed to detect and monitor this disease, none has the requisite sensitivity to identify it at a preclinical stage or to perceive small changes in retinal health over short periods. Specifically, irreversible visual changes occur before neuronal damage is discovered. The most widely accepted in vitro assay for apoptotic cells involves the use of fluorescent annexin A5. The radiolabelling of this marker makes it possible to assess, in vivo and non-invasively, various diseases in which the apoptotic process is pivotal, such as myocardial infarction or tumour response to chemotherapy. Recently, a new technique has been developed to visualise directly individual RGCs undergoing apoptosis in the living eye. This DARC (detection of apoptosing retinal cells) technology uses fluorescently labelled annexin A5 to bind apoptosing retinal neurons and confocal scanning laser ophthalmoscopy to detect the marked dying cells. Based on experimental models, DARC has been suggested to offer a direct and quantitative assessment of the retinal condition of patients. A Phase I clinical trial in glaucoma patients is scheduled to start shortly. This technology has the potential to pre-empt the diagnosis of glaucoma prior to visual deterioration, to provide an accurate numeric evaluation highlighting even small retinal changes and to allow the rapid judgement of the efficacy of both current and new therapeutic strategies.

Biobanking in health care has evolved over the last few decades from simple biological sample repositories to complex and dynamic units with multi‐organizational infrastructure networks and has become an essential tool for modern medical research. Cardiovascular tissue biobanking provides a unique opportunity to utilize cardiac and vascular samples for translational research into heart failure and other related pathologies. Current techniques for diagnosis, classification, and treatment monitoring of cardiac disease relies primarily on interpretation of clinical signs, imaging, and blood biomarkers. Further research at the disease source (i.e. myocardium and blood vessels) has been limited by a relative lack of access to quality human cardiac tissue and the inherent shortcomings of most animal models of heart disease. In this review, we describe a model for cardiovascular tissue biobanking and databasing, and its potential to facilitate basic and translational research. We share techniques to procure endocardial samples from patients with hypertrophic cardiomyopathy, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, in addition to aortic disease samples. We discuss some of the issues with respect to data collection, privacy, biobank consent, and the governance of tissue biobanking. The development of tissue biobanks as described here has significant scope to improve and facilitate translational research in multi‐omic fields such as genomics, transcriptomics, proteomics, and metabolomics. This research heralds an era of precision medicine, in which patients with cardiovascular pathology can be provided with optimized and personalized medical care for the treatment of their individual phenotype.

Neurofibromin, coded by the tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. To accurately model the germline monoallelic mutations in NF1 patients, we utilized an deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer. We identified increased collagen content in -deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that -deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance. Collectively, this study uncovered the previously undescribed role of in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.