Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1^−/D mice). Ckmm-Cre^+/−;Ercc1^−/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre^+/−;Ercc1^−/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre^+/-;Ercc1^−/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre^+/−;Ercc1^−/fl and Ercc1^−/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.     

The mouse Dlx-2 (Tes-1) gene is expressed in spatially restricted domains of the forebrain, face and limbs in midgestation mouse embryos

The pattern of RNA expression of the murine Dlx-2 (Tes-1) homeobox gene is described in embryos ranging in age from E8.5 through E11.5. Dlx-2 is a vertebrate homologue of the Drosophila Distal-less (Dll) gene. Dll expression in the Drosophila embryo is principally limited to the primordia of the brain, head and limbs. Dlx-2 is also expressed principally in the primordia of the forebrain, head and limbs. Within these regions it is expressed in spatially restricted domains. These include two discontinuous regions of the forebrain (basal telencephalon and ventral diencephalon), the branchial arches, facial ectoderm, cranial ganglia and limb ectoderm. Several mouse and human disorders have phenotypes which potentially are the result of mutations in the Dlx genes.     

Mapping and monitoring tick (Acari,Ixodida) distribution,seasonality, and host associations in the United Kingdom between 2017 and 2020

Tick-borne disease risk is intrinsically linked to the distribution of tick vector species. To assess risk and anticipate disease emergence, an understanding of tick distribution, host associations, and seasonality is needed. This can be achieved, to some extent, using passive surveillance supported by engagement with the public, animal health, and public health experts. The Tick Surveillance Scheme (TSS) collects data and maps tick distribution across the United Kingdom (UK). Between 2017 and 2020, 3720 tick records were received and 39 tick species were detected. Most records were acquired in the UK, with a subset associated with recent overseas travel. The dominant UK acquired species was Ixodes ricinus (Ixodida: Ixodidae, Linnaeus), the main vector of Lyme borreliosis. Records peaked during May and June, highlighting a key risk period for tick bites. Other key UK species were detected, including Dermacentor reticulatus (Ixodida: Ixodidae, Fabricius) and Haemaphysalis punctata (Ixodida: Ixodidae, Canestrini & Fanzago) as well as several rarer species that may present novel tick-borne disease risk to humans and other animals. Updated tick distribution maps highlight areas in the UK where tick exposure has occurred. There is evidence of increasing human tick exposure over time, including during the COVID-19 pandemic, but seasonal patterns remain unchanged.     

Oxide-Based Solid-State Batteries: A Perspective on Composite Cathode Architecture

The garnet-type phase Li₇La₃Zr₂O₁₂ (LLZO) attracts significant attention as an oxide solid electrolyte to enable safe and robust solid-state batteries (SSBs) with potentially high energy density. However, while significant progress has been made in demonstrating compatibility with Li metal, integrating LLZO into composite cathodes remains a challenge. The current perspective focuses on the critical issues that need to be addressed to achieve the ultimate goal of an all-solid-state LLZO-based battery that delivers safety, durability, and pack-level performance characteristics that are unobtainable with state-of-the-art Li-ion batteries. This perspective complements existing reviews of solid/solid interfaces with more emphasis on understanding numerous homo- and heteroionic interfaces in a pure oxide-based SSB and the various phenomena that accompany the evolution of the chemical, electrochemical, structural, morphological, and mechanical properties of those interfaces during processing and operation. Finally, the insights gained from a comprehensive literature survey of LLZO–cathode interfaces are used to guide efforts for the development of LLZO-based SSBs.     

Induction of programmed cell death in a dorsal root ganglia × neuroblastoma cell line

Growth factor-dependent neurons die when they are deproved of their specific growth factor. This “programmed” cell death (PCD) requires macromolecular synthesis and is distinct from necrotic cell death. To investigate the mechanisms involved in neuronal PCD, we have studied the sequence of events that occur when a neuronal cell line (F-11: Mouse neuroblastoma X rat dorsal root ganglia) is deprived of serum in a manner analogous to growth factor deprivation from neurons. Protein synthesis was inhibited within the first 8 h of serum deprivation, while DNA cleavage into nucleosome ladders was prominent by 24 h. The DNA cleavage could be inhibited by cycloheximide, consistent with a requirement for protein synthesis. In contrast, mitochondrial function was not compromised by serum deprivation. Rather, the cells appeared to be metabolically activated after serum removal as shown by an increased reduction of MTT by mitochondrial dehydrogenases and an increase in cellular autofluorescence, which is thought to be due to elevated levels of NADH and flavoproteins. Assessment of cell viability by propidium iodide staining showed no indication of cell death within 24 h. After 48 h of serum deprivation, cells decreased in size and increased propidium iodide uptake. Thus, serum deprivation activates PCD in F-11 cells and may be a useful model to study the intracellular events responsible for PCD. © 1993 John Wiley & Sons, Inc.     

Applying single-cell highly multiplexed secretome proteomics to characterize immunotherapeutic products and predict clinical responses

Genetically and phenotypically identical immune cell populations can be highly heterogenous in terms of their immune functions and protein secretion profiles. The microfluidic chip-based single-cell highly multiplexed secretome proteomics enables characterization of cellular heterogeneity of immune responses at different cellular and molecular layers. Increasing evidence has demonstrated that polyfunctional T cells that simultaneously produce 2+ proteins per cell at the single-cell level are key effector cells that contribute to the development of potent and durable cellular immunity against pathogens and cancers. The functional proteomic technology offers a wide spectrum of cellular function assessment and can uniquely define highly polyfunctional cell subsets with cytokine signatures from live individual cells. This high-dimensional single-cell analysis provides deep dissection into functional heterogeneity and helps identify predictive biomarkers and potential correlates that are crucial for immunotherapeutic product design optimization and personalized immunotherapy development to achieve better clinical outcomes.     

Physostigmine: dose-response effects on endurance and thermoregulation during exercise.

We previously reported that the administration of 200 micrograms/kg of physostigmine (PH) to rats exercising on a treadmill resulted in decrements in both endurance (decreased running time to exhaustion) and thermoregulation. However, it was necessary to determine the dose-response effects of PH administration before PH-treated exercising rats could be used as a model with which to examine the relative anticholinergic potency of drugs. In the present work saline, 50, 100, or 200 micrograms/kg of physostigmine salicylate (0%, 40%, 50%, and 60% whole blood cholinesterase inhibition) was administered to rats (N = 12/group) prior to treadmill exercise (26 degrees C, 50% rh, 11 m/min, 6 degrees incline). The saline control group ran for 67 +/- 6 min (mean +/- SE) with a rate of rise of core temperature of 0.051 +/- 0.007 degrees C/min. The run times declined (80%, 64% and 48% of control) as rate of rise of core temperature increased (116%, 180%, and 214% of control) in a dose-dependent manner (50, 100, 200 micrograms/kg PH). Cholinergic symptoms such as salivation, tremors, and defecation were also affected in a dose-dependent manner by PH administration. Since cholinergic symptoms, thermoregulatory effects, and endurance decrements all vary in a dose-dependent manner with physostigmine administration, the exercising rat represents a useful model for examining the relative potency of cholinergic therapies.     

DISEASE IMPACT AND LOCAL GENETIC DIVERSITY IN THE CLONAL PLANT PODOPHYLLUM PELTATUM

Genotypic diversity is restricted within local colonies of mayapple (Podophyllum peltatum), due to extensive asexual reproduction. Transplant experiments were used to examine whether disease impact from a specialist fungal pathogen (Puccinia podophylli) was affected by the local frequency of host genotypes within colonies. In each of six large mayapple colonies, I measured infection intensity on 1) ramets replanted in their native colony (which were thus surrounded mostly by identical genotypes) and 2) transplants from two foreign colonies (surrounded by different genotypes). Disease incidence during the pathogen's first generation did not vary significantly between native (11% infected) and foreign host genotypes (6% infected). In the pathogen's second generation, significant variation in infection intensity occurred among ramets from different source populations. However, at five of the six transplant sites, mean infection intensity was higher on some nonnative plants (locally rare host genotypes) than on natives (locally common host genotypes). In this system, pathogen attack does not act in a frequency-dependent manner to promote local genetic diversity among hosts.     

Testing the ecological relevance of Daphnia species designations

1. Molecular approaches have increasingly revealed hidden genetic structure within ecologically important species, leading to the creation of sibling species whose ecological relevance is often unclear. A prime example is Daphnia galeata mendotae, which was split into D. dentifera and D. mendotae based on differences at two allozyme loci. 2. In a set of lake populations in Michigan USA, we test the geographical and temporal consistency of the genetic structure underlying this species split. We also test the morphological relevance of this molecular variation and its ecological significance in lakes. In essence, we ask: does recognition of these new species provide valuable information for plankton ecologists? 3. We found that D. dentifera and D. mendotae represent morphologically and ecologically distinct forms that are distributed among lakes in non‐random fashion, which were remarkably stable over 6 years. Key differences between the species concern their body and head shape, vertical habitat use within lakes and distribution among lakes of different size. We hypothesise that these differences represent specialisation to habitats that differ in risk of invertebrate predation. 4. Reproductive barriers alone are insufficient to explain the pattern of genetic structure; in some lakes complete introgression is apparent. However, parent species and hybrids exhibit a stable co‐existence in many lakes, which suggests that ecological specialisation reinforces divergence within this taxon.     

North Sea cod and climate change – modelling the effects of temperature on population dynamics

In order to examine the likely impacts of climate change on fish stocks, it is necessary to couple the output from large‐scale climate models to fisheries population simulations. Using projections of future North Sea surface temperatures for the period 2000–2050 from the Hadley General Circulation Model, we estimate the likely effects of climate change on the North Sea cod population. Output from the model suggests that increasing temperatures will lead to an increased rate of decline in the North Sea cod population compared with simulations that ignore environmental change. Although the simulation developed here is relatively simplistic, we demonstrate that inclusion of environmental factors in population models can markedly alter one's perception of how the population will behave. The development of simulations incorporating environment effects will become increasingly important as the impacts of climate change on the marine ecosystem become more pronounced.