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A fluorogenic platform for real-time imaging of subcellular payload release in antibody-drug conjugates
Get PDFAntibody-drug conjugates (ADCs) represent promising therapeutic constructs to enhance the selective delivery of drugs to target cells; however, attaining precise control over the timing and location of payload release remains challenging due to the complex intracellular processes that define ADC internalization, trafficking and linker cleavage. In this study, we present novel real-time fluorogenic probes to monitor both subcellular dynamics of ADC trafficking and payload release. We optimized a tandem molecular design of sequential pH- and enzyme-activatable naphthalimide fluorophores to 1) track their subcellular localization along the endolysosomal pathway and 2) monitor linker cleavage with OFF-to-ON fluorescence switches. Live-cell imaging microscopy revealed that fluorogenic ADCs can traffic to the lysosomes, and yet require residence time in these subcellular compartments for efficient linker cleavage. Notably, the compact size of fluorogenic naphthalimides did not impair the recognition of target cell-surface reporters or the kinetics of payload release. This modular platform is applicable to many ADCs and holds promise to inform their rational design for optimal release profiles and therapeutic efficacy
WAND:A multi-modal dataset integrating advanced MRI, MEG, and tMS for multi-scale brain analysis
Get PDFThis paper introduces the Welsh Advanced Neuroimaging Database (WAND), a multi-scale, multi-modal imaging dataset comprising in vivo brain data from 170 healthy volunteers (aged 18-63 years), including 3 Tesla (3 T) magnetic resonance imaging (MRI) with ultra-strong (300 mT/m) magnetic field gradients, structural and functional MRI and nuclear magnetic resonance spectroscopy at 3 T and 7 T, magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS), together with trait questionnaire and cognitive data. Data are organised using the Brain Imaging Data Structure (BIDS). In addition to raw data, we provide brain-extracted T1-weighted images, and quality reports for diffusion, T1- and T2-weighted structural data, and blood-oxygen level dependent functional tasks. Reasons for participant exclusion are also included. Data are available for download through our GIN repository, a data access management system designed to reduce storage requirements. Users can interact with and retrieve data as needed, without downloading the complete dataset. Given the depth of neuroimaging phenotyping, leveraging ultra-high-gradient, high-field MRI, MEG and TMS, this dataset will facilitate multi-scale and multi-modal investigations of the healthy human brain
Understanding how violence is transmitted across generations? An in-depth multiple case study of families in South Africa
Get PDFObjective: Interpersonal violence is a major public health issue, particularly in low-resource contexts like South Africa, where it is pervasive. Understanding the contextual risk for intergenerational transmission of violence (ITV) is vital for a nuanced approach to prevention and intervention. This study sought to understand the risks that drive ITV across multiple generations and within the same families in a community in South Africa. Method: Drawing from the third phase of a longitudinal cohort study, participants experiencing violence were purposively sampled and interviews were conducted at two time points with young adults, their oldest child and their former caregivers in seven multigenerational families (n=38 interviews). Results: Using a multiple case study design, findings of risks for ITV were grounded in these themes: 1) unresolved aggression reenacted in the next generation, 2) complicated parenting arrangements leading to challenging attachment relationships across generations, and 3) subscription to inflexible injunctive norms causing marginalization across generations. Central to all these themes was reenactment of the past in the present and significant underlying vulnerability in families characterized by violence transmission. The violence of the past and the present was rooted in ongoing structural drivers of violence, including poverty, food insecurity, unemployment or underemployment, poor mental health, poor services (of justice, health, education, child protection) and poor understanding of child and adolescent development. Conclusions: Comprehending how violence is transmitted within the same families and across multiple generations offers insight on the risks of ITV to create more targeted prevention and intervention efforts to curb it
Between dissatisfaction and support:Justificatory repertoires in public feedback on emergency healthcare in the United Kingdom National Health Service
Get PDFQuantitative studies of public opinion on healthcare often distinguish between support for the system and satisfaction with its services. The relationship between these two dimensions can appear contradictory: in UK surveys strong support for the NHS co-exists with rising dissatisfaction with care quality. We investigate this apparent contradiction through a novel analysis of 169 critical reviews of emergency care visits in the UK submitted to the Care Opinion platform between 2015 and 2023. While reviews all describe instances of poor care, we identify the ‘justificatory repertoires’ through which reviewers express continued support for the NHS. We argue this reveals how societal attitudes towards public healthcare provision are in a recursive relationship with actual experiences of healthcare, and that the articulation of those experiences is deeply shaped by awareness of the broader political context. Analysis of patient narratives reveals complex relationships between solidarity and dissatisfaction in public opinion, and insights into policy feedback loops between healthcare provision, institutional design and public attitudes toward healthcare
Linking higher amyloid beta 1-38 (Aβ(1-38)) levels to reduced Alzheimer's disease progression risk
Get PDFINTRODUCTION: The beneficial effects of amyloid beta 1-38, or Aβ(1-38), on Alzheimer's disease (AD) progression in humans in vivo remain controversial. We investigated AD patients' cerebrospinal fluid (CSF) Aβ(1-38) and AD progression.METHODS: Cognitive function and diagnostic change were assessed annually for 3 years in 177 Aβ-positive participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia from the German Center for Neurodegenerative Diseases (DZNE) longitudinal cognitive impairment and dementia study (DELCODE) cohort using the Mini-Mental State Examination (MMSE), Preclinical Alzheimer's Cognitive Composite (PACC), Clinical Dementia Rating (CDR), and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Mixed linear and Cox regression analyses were conducted. CSF was collected at baseline.RESULTS: Higher Aβ(1-38) levels were associated with slower PACC (p = 0.001) and slower CDR Sum of Boxes (CDR-SB) (p = 0.002) but not MMSE decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed an association of Aβ(1-38) with slower PACC decline (p = 0.005), but not with CDR-SB or MMSE decline. In addition, higher Aβ(1-38) baseline levels were associated with a reduced dementia conversion risk.DISCUSSION: Further research is needed to understand the role of Aβ(1-38) in AD and its potential for future therapeutic strategies.HIGHLIGHTS: This study not only replicates but also extends the existing findings on the role of Aβ(1-38) (amyloid beta 1-38) in Alzheimer's disease (AD) in humans in vivo. Higher baseline Aβ(1-38) levels were associated with a decreased risk of conversion to AD dementia in subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Different linear-mixed regression models suggest an association between higher Aβ(1-38) baseline levels and slower Preclinical Alzheimer's Cognitive Composite (PACC) and Clinical Dementia Rating Sum of Boxes (CDR-SB) decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed a link between Aβ(1-38) and PACC decline, but showed no association of Aβ(1-38) on CDR-SB and Mini-Mental State Examination (MMSE) decline. The impact of short Aβ isoforms in AD progression might have been under-investigated These findings underscore the urgent need for additional research on the role of these shorter Aβ peptides in AD, as they may hold key insights for future therapeutic strategies.</p
Accelerated Diagnostic Pathways for Myocardial Infarction Using a Siemens High-Sensitivity Cardiac Troponin I Assay
Get PDFBackground: Few studies have comprehensively examined high-sensitivity cardiac troponin I (hs-cTnI) based diagnostic pathways for myocardial infarction (MI) in early presenters using a Siemens ADVIA Centaur hs-cTnI assay.Methods: We conducted a prospective multicenter cohort study in Emergency Departments involving 414 patients suspected of MI within 6 hours of symptom onset. We evaluated three hs-cTnI-based pathways (High-STEACS, ESC 0/1-h, 0/2-h); and four pathways incorporating medical history and physical findings (ADAPT, EDACS, HEART, GRACE). We evaluated negative predictive value (NPV) and sensitivity as safety measures, and percentage ruled out as an efficiency measure for a primary outcome of type 1 myocardial infarction or cardiac death within 30 days.Results: Median age was 72 years (interquartile range 58-82), and 30.4% (126/414) of patients were over 80. Females comprised 44.2% (183/414) of patients, 87.7% (363/414) had chest pain, and the primary outcome occurred in 9.2% (38/414). The High-STEACS pathway ruled out 62.0% of patients without missing a case of an MI. The ESC 0/1-h and 0/2-h pathways showed high NPV and sensitivities; however, they ruled out fewer patients (35.9% and 45.2%, respectively). The ADAPT, EDACS, and HEART pathways demonstrated high NPV and sensitivities but ruled out fewer patients (15-27%). The GRACE pathway missed 2 cases with primary clinical outcomes. Among patients over 80 without MI, initial hs-cTnI concentration was ≥3 ng/L in 99.1% and ≥5 ng/L in 84.1%.Conclusions: The High-STEACS pathway was the most efficient among the hs-cTnI-based pathways while maintaining excellent safety performance in early presenters. <br/
Foundations of anonymous signatures:Formal definitions, simplified requirements, and a construction based on general assumptions
Get PDFIn today’s systems, privacy is often at odds with utility: users that reveal little information about themselves get restricted functionality, and service providers mistrust them. In practice, systems tip to either full anonymity (e.g. Monero), or full utility (e.g. Bitcoin). Well-known cryptographic primitives for bridging this gap exist: anonymous credentials (AC) let users disclose a subset of their credentials’ attributes, revealing to service providers “just what they need”; group signatures (GS) allow users to authenticate anonymously, to be de-anonymized “just when deemed necessary”. However, these primitives are hard to deploy.Current AC and GS variants reach specific points in the privacy-utility tradeoff, which we point as counter-productive engineering-wise, as it requires full and error-prone re-engineering to adjust the tradeoff. Also, so far, GS and AC have been studied separately by theoretical research.We take the first steps toward unifying and generalizing both domains, with the goal of bringing their benefits to practice, in a flexible way. We give a common model capturing their core properties, and use functional placeholders to subsume intermediate instantiations of the privacy-utility tradeoff under the same model. To prove its flexibility, we show how concrete variants of GS, AC (and others, like ring signatures) can be seen as special cases of our scheme – to which we refer as universal anonymous signatures (UAS). In practice, this means that instantiations following our construction can be configured to behave as variant X of a GS scheme, or as variant Y of an AC scheme, by tweaking a few functions
A high energy resolution gas target setup to study selected NeNa cycle reactions
Get PDFThe neon-sodium cycle of hydrogen burning occurs in several astrophysical sites, such as asymptotic giant branch stars and novae, affecting the production of neon and sodium isotopes. To enhance the accuracy of predicted nucleosynthesis yields, there is a pressing need fornew experimental investigations of the cross sections of the reactions involved in this cycle at energies relevant to astrophysics. The 400 kV accelerator at the Laboratory for Underground Nuclear Astrophysics (LUNA) provides a unique advantage relative to above-ground laboratories thanks to itsdeep underground location within the Gran Sasso National Laboratory (INFN-LNGS) in Italy. We performed experiments at LUNA on two of the reactions of the NeNa cycle: 20Ne(p,γ )21Na and 21Ne(p,γ )22Na using a high-purity gas target system for isotopically enriched gases coupled withtwo high-resolution germanium detectors, surrounded by copper and lead shielding to further reduce the natural background at LUNA. We describe the detailed characterization of the experimental setup performed through Monte Carlo simulations, and the method for the precise determination of resonance energies, giving improved values of Er = 127.3 ±0.5 keV, 271.4 ± 0.4 keV, 272.3 ± 0.4 keV, 291.5 ± 0.5 keV and 352.6 ± 0.4 keV. Additionally, decay branching ratios for the Ex = 7016.4 keV excited state in 22Na, and three new transitions (R → 4770 keV, R → 3059.4 keV andR → 583.05 keV) in the Er = 291.5 keV resonance, are also reported
Theileria annulata infects B-cells in sheep, which display lower dissemination potential compared to T. lestoquardi-infected ovine B-cells
No full textTheileria annulata and Theileria lestoquardi are deadly tick-borne parasites of cattle and sheep, respectively. These parasites are transmitted by Hyalomma ticks, and their geographical distributions partially overlap, with T. annulata having a wider range. Theileria lestoquardi infection is highly pathogenic in its natural sheep and goat hosts while T. annulata infection usually causes a mild disease in these species. Interestingly, T. annulata does not produce merozoites/piroplasms in sheep and goats, therefore it is not tick-transmissible. The aim of the current study was to understand the basis of the attenuated pathogenicity of ovine infections by T. annulata. Theileria annulata and T. lestoquardi sporozoites were used to infect sheep and parasitized ovine leukocytes were isolated and phenotyped. This revealed that T. annulata sporozites target ovine B-cells, whereas T. lestoquardi sporozoite infection was not restricted to ovine B-cells. The ability of ovine B-cells infected with T. lestoquardi or T. annulata to traverse Matrigel in vitro was investigated, as a surrogate for their ability to disseminate in vivo and cause disease. The Matrigel traversal index of T. lestoquardi-transformed ovine B-cells was significantly higher than that of T. annulata-transformed ovine B-cells isolated from the same host, consistent with the reported diminished pathogenicity of T. annulata infections in sheep. Theileria lestoquardi-transformed ovine B-cells preferentially expressed matrix metalloproteinase 2 (mmp2), whereas T. annulata-infected ovine B-cells strongly expressed mmp9. Correspondingly, MMP9 protein levels and collagenase activity were higher in T. annulata-transformed ovine B-cells. However, T. annulata-transformed ovine B-cells expressed higher levels of transcripts for Tissue Inhibitor of Metallopeptidases 1 and 2 (TIMP1 and TIMP2). TIMPs are the natural endogenous inhibitors of MMPs. This argues that their heightened expression could underpin the significantly lower Matrigel traversal activity of T. annulata-infected compared to T. lestoquardi-infected ovine B-cells.</p
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