Cyanine dye mediated mitochondrial targeting enhances the anti-cancer activity of small-molecule cargoes

Organelle-specific delivery systems are of significant clinical interest. We demonstrate the use of common cyanine dyes Cy3 and Cy5 as vectors for targeting and delivering cargoes to mitochondria in cancer cells. Specifically, conjugation to the dyes can increase cytotoxicity by up to 1000-fold

Video and Synthetic MRI Pre-training of 3D Vision Architectures for Neuroimage Analysis

Transfer learning represents a recent paradigm shift in the way we build artificial intelligence (AI) systems. In contrast to training task-specific models, transfer learning involves pre-training deep learning models on a large corpus of data and minimally fine-tuning them for adaptation to specific tasks. Even so, for 3D medical imaging tasks, we do not know if it is best to pre-train models on natural images, medical images, or even synthetically generated MRI scans or video data. To evaluate these alternatives, here we benchmarked vision transformers (ViTs) and convolutional neural networks (CNNs), initialized with varied upstream pre-training approaches. These methods were then adapted to three unique downstream neuroimaging tasks with a range of difficulty: Alzheimer's disease (AD) and Parkinson's disease (PD) classification, "brain age" prediction. Experimental tests led to the following key observations: 1. Pre-training improved performance across all tasks including a boost of 7.4% for AD classification and 4.6% for PD classification for the ViT and 19.1% for PD classification and reduction in brain age prediction error by 1.26 years for CNNs, 2. Pre-training on large-scale video or synthetic MRI data boosted performance of ViTs, 3. CNNs were robust in limited-data settings, and in-domain pretraining enhanced their performances, 4. Pre-training improved generalization to out-of-distribution datasets and sites. Overall, we benchmarked different vision architectures, revealing the value of pre-training them with emerging datasets for model initialization. The resulting pre-trained models can be adapted to a range of downstream neuroimaging tasks, even when training data for the target task is limited

Adverse Childhood Experiences and Adult Cardiometabolic Risk Factors and Disease Outcomes: Cross-Sectional, Populationbased Study of Adults in Rural Uganda

Background: Cardiovascular diseases (CVD) pose a major threat to public health in sub-Saharan African communities, where the burden of these classes of illnesses is expected to double by 2030. Growing research suggests that past developmental experiences and early life conditions may also elevate CVD risk throughout the life course. Greater childhood stress and adversity are consistently associated with a range of adult CVDs and associated risk factors, yet little research exists on the long-term effects of early life stress on adult physical health outcomes, especially CVD risk, in sub-Saharan African contexts. This study aims to evaluate the associations between adverse childhood experiences and adult cardiometabolic risk factors and health outcomes in a population-based study of adults living in Mbarara, a rural region of southwestern Uganda. Methods Data come from an ongoing, whole-population social network cohort study of adults living in the eight villages of Nyakabare Parish, Mbarara. A modified version of the Adverse Childhood Experiences-International Questionnaire (ACEs) assessed past exposure to physical, emotional, and sexual adversity. Participants also took part in a health fair where medical histories on cardiometabolic risk factors and cardiovascular diseases were gathered. Multiple logistic regression models estimated the associations between ACEs and cardiometabolic risk factors and health outcomes. Results Data were available on 545 adults. The average number of ACEs was 4.9 out of a possible 16. The cumulative number of ACEs were associated with having a history of heart attack and/or heart failure (adjusted odds ratio (AOR) = 1.11, 95% confidence interval (CI) = 0.999-1.234, P = 0.051), but the estimated association was not statistically significant. ACEs did not have statistically significant associations with any others measures of adult cardiometabolic risk and CVD. Conclusions: Adverse childhood experiences are not associated with a range of adult cardiometabolic risk factors and health outcomes in this sample of rural Ugandan adults. Further research in this sample is necessary to identify the pathways that may motivate these null relationship and possibly protect against adverse cardiometabolic and cardiovascular health outcomes

Wild bitter gourd improves metabolic syndrome: A preliminary dietary supplementation trial

<p>Abstract</p> <p>Background</p> <p>Bitter gourd (<it>Momordica charantia </it>L.) is a common tropical vegetable that has been used in traditional or folk medicine to treat diabetes. Wild bitter gourd (WBG) ameliorated metabolic syndrome (MetS) in animal models. We aimed to preliminarily evaluate the effect of WBG supplementation on MetS in Taiwanese adults.</p> <p>Methods</p> <p>A preliminary open-label uncontrolled supplementation trial was conducted in eligible fulfilled the diagnosis of MetS from May 2008 to April 2009. A total of 42 eligible (21 men and 21 women) with a mean age of 45.7 ± 11.4 years (23 to 63 years) were supplemented with 4.8 gram lyophilized WBG powder in capsules daily for three months and were checked for MetS at enrollment and follow-up monthly. After supplementation was ceased, the participants were continually checked for MetS monthly over an additional three-month period. MetS incidence rate were analyzed using repeated-measures generalized linear mixed models according to the intention-to-treat principle.</p> <p>Results</p> <p>After adjusting for sex and age, the MetS incidence rate (standard error, <it>p </it>value) decreased by 7.1% (3.7%, 0.920), 9.5% (4.3%, 0.451), 19.0% (5.7%, 0.021), 16.7% (5.4%, 0.047), 11.9% (4.7%, 0.229) and 11.9% (4.7%, 0.229) at visit 2, 3, 4, 5, 6, and 7 compared to that at baseline (visit 1), respectively. The decrease in incidence rate was highest at the end of the three-month supplementation period and it was significantly different from that at baseline (<it>p </it>= 0.021). The difference remained significant at end of the 4th month (one month after the cessation of supplementation) (<it>p </it>= 0.047) but the effect diminished at the 5th and 6th months after baseline. The waist circumference also significantly decreased after the supplementation (<it>p </it>< 0.05). The WBG supplementation was generally well-tolerated.</p> <p>Conclusion</p> <p>This is the first report to show that WBG improved MetS in human which provides a firm base for further randomized controlled trials to evaluate the efficacy of WBG supplementation.</p

Rad Regulation of CaV12 Channels Controls Cardiac Fight-or-Flight Response

Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart\u27s innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for β-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of β-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel β-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility

Dopamine neurons modulate neural encoding and expression of depression-related behaviour

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry

Cell-penetrating peptide sequence and modification dependent uptake and subcellular distribution of green florescent protein in different cell lines

Protein therapy holds great promise for treating a variety of diseases. To act on intracellular targets, therapeutic proteins must cross the plasma membrane. This has previously been achieved by covalent attachment to a variety of cell-penetrating peptides (CPPs). However, there is limited information on the relative performance of CPPs in delivering proteins to cells, specifically the cytosol and other intracellular locations. Here we use green fluorescent protein (GFP) as a model cargo to compare delivery capacity of five CPP sequences (Penetratin, R8, TAT, Transportan, Xentry) and cyclic derivatives in different human cell lines (HeLa, HEK, 10T1/2, HepG2) representing different tissues. Confocal microscopy analysis indicates that most fusion proteins when incubated with cells at 10 µM localise to endosomes. Quantification of cellular uptake by flow cytometry reveals that uptake depends on both cell type (10T1/2 > HepG2 > HeLa > HEK), and CPP sequence (Transportan > R8 > Penetratin≈TAT > Xentry). CPP sequence cyclisation or addition of a HA-sequence increased cellular uptake, but fluorescence was still contained in vesicles with no evidence of endosomal escape. Our results provide a guide to select CPP for endosomal/lysosomal delivery and a basis for developing more efficient CPPs in the future

Transmission Characteristics of the 2009 H1N1 Influenza Pandemic: Comparison of 8 Southern Hemisphere Countries

While in Northern hemisphere countries, the pandemic H1N1 virus (H1N1pdm) was introduced outside of the typical influenza season, Southern hemisphere countries experienced a single wave of transmission during their 2009 winter season. This provides a unique opportunity to compare the spread of a single virus in different countries and study the factors influencing its transmission. Here, we estimate and compare transmission characteristics of H1N1pdm for eight Southern hemisphere countries/states: Argentina, Australia, Bolivia, Brazil, Chile, New Zealand, South Africa and Victoria (Australia). Weekly incidence of cases and age-distribution of cumulative cases were extracted from public reports of countries' surveillance systems. Estimates of the reproduction numbers, R0, empirically derived from the country-epidemics' early exponential phase, were positively associated with the proportion of children in the populations (p = 0.004). To explore the role of demography in explaining differences in transmission intensity, we then fitted a dynamic age-structured model of influenza transmission to available incidence data for each country independently, and for all the countries simultaneously. Posterior median estimates of R0 ranged 1.2–1.8 for the country-specific fits, and 1.29–1.47 for the global fits. Corresponding estimates for overall attack-rate were in the range 20–50%. All model fits indicated a significant decrease in susceptibility to infection with age. These results confirm the transmissibility of the 2009 H1N1 pandemic virus was relatively low compared with past pandemics. The pattern of age-dependent susceptibility found confirms that older populations had substantial – though partial - pre-existing immunity, presumably due to exposure to heterologous influenza strains. Our analysis indicates that between-country-differences in transmission were at least partly due to differences in population demography

Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells

In utero hematopoietic cell transplantation (IUHCT) is a potential therapy for the treatment of numerous genetic diseases such as hemoglobinopathies, immunodeficiencies, and inborn errors of metabolism.1 In utero therapy offers the benefit of avoiding host myeloablation and immunosuppression and has been shown to be successful in multiple animal models, including mice,2-5 dogs,6,7 pigs,8,9 and sheep.10-12 The timing of IUHCT exposes the transplanted human cells to the normal fetal migratory and developmental cues that facilitate proper stem cell distribution and differentiation.11,12 Clinically, IUHCT has been successful for fetuses with severe combined immunodeficiency (SCID),13,14 but therapeutic uses for other diseases, including hemoglobinopathies, have seen limited success.15 Further investigations identified multiple barriers to successful engraftment, including lack of space within the hematopoietic niche16,17 and the maternal immune system.2,18 Among available animal models of IUHCT, the fetal mouse remains an efficient and reproducible model to study the differentiation of stem cells in a nonirradiated host. NSG (NOD-SCID IL2Rg-null) mice, which are developed with SCID and IL-2Rg-null chain mutations, are a robust platform for the engraftment of human hematopoietic cells because they have no endogenous T, B, or natural killer cells.19-22 In this study, we used IUHCT of human CD341 cells in NSG mice to create a reproducible mouse model to study stem cell engraftment, differentiation, and systemic repopulation after IUHCT