Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network ...analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.
The recognition of anions in water remains a key challenge in modern supramolecular chemistry, and is essential if proposed applications in biological, medical, and environmental arenas that ...typically require aqueous conditions are to be achieved. However, synthetic anion receptors that operate in water have, in general, been the exception rather than the norm to date. Nevertheless, a significant step change towards routinely conducting anion recognition in water has been achieved in the past few years, and this Review highlights these approaches, with particular focus on controlling and using the hydrophobic effect, as well as more exotic interactions such as C−H hydrogen bonding and halogen bonding. We also look beyond the field of small‐molecule recognition into the macromolecular domain, covering recent advances in anion recognition based on biomolecules, polymers, and nanoparticles.
The quest for recognition: The recognition of anions in water is a great challenge for supramolecular chemistry. Recently, great strides have been made in this area by exploiting exotic interactions such as C−H hydrogen bonding and halogen bonding, as well as exercising control over the hydrophobic effect. Recognition strategies based on biomolecules, polymers, and nanoparticles also offer a complementary approach to anion binding in the aqueous phase.
The role of the ERK signalling pathway in cancer is thought to be most prominent in tumours in which mutations in the receptor tyrosine kinases RAS, BRAF, CRAF, MEK1 or MEK2 drive growth ...factor-independent ERK1 and ERK2 activation and thence inappropriate cell proliferation and survival. New drugs that inhibit RAF or MEK1 and MEK2 have recently been approved or are currently undergoing late-stage clinical evaluation. In this Review, we consider the ERK pathway, focusing particularly on the role of MEK1 and MEK2, the 'gatekeepers' of ERK1/2 activity. We discuss their validation as drug targets, the merits of targeting MEK1 and MEK2 versus BRAF and the mechanisms of action of different inhibitors of MEK1 and MEK2. We also consider how some of the systems-level properties (intrapathway regulatory loops and wider signalling network connections) of the ERK pathway present a challenge for the success of MEK1 and MEK2 inhibitors, discuss mechanisms of resistance to these inhibitors, and review their clinical progress.
Lung cancer (LC) is the most prevalent cancer worldwide, and responsible for over 1.3 million deaths each year. Currently, LC has a low five year survival rates relative to other cancers, and thus, ...novel methods to screen for and diagnose malignancies are necessary to improve patient outcomes. Here, we report on a pilot-sized study to evaluate the potential of the sputum microbiome as a source of non-invasive bacterial biomarkers for lung cancer status and stage. Spontaneous sputum samples were collected from ten patients referred with possible LC, of which four were eventually diagnosed with LC (LC+), and six had no LC after one year (LC-). Of the seven bacterial species found in all samples, Streptococcus viridans was significantly higher in LC+ samples. Seven further bacterial species were found only in LC-, and 16 were found only in samples from LC+. Additional taxonomic differences were identified in regards to significant fold changes between LC+ and LC-cases, with five species having significantly higher abundances in LC+, with Granulicatella adiacens showing the highest level of abundance change. Functional differences, evident through significant fold changes, included polyamine metabolism and iron siderophore receptors. G. adiacens abundance was correlated with six other bacterial species, namely Enterococcus sp. 130, Streptococcus intermedius, Escherichia coli, S. viridans, Acinetobacter junii, and Streptococcus sp. 6, in LC+ samples only, which could also be related to LC stage. Spontaneous sputum appears to be a viable source of bacterial biomarkers which may have utility as biomarkers for LC status and stage.
Electronic nicotine delivery systems (ENDS) or e-cigarettes have emerged as a popular recreational tool among adolescents and adults. Although the use of ENDS is often promoted as a safer alternative ...to conventional cigarettes, few comprehensive studies have assessed the long-term effects of vaporized nicotine and its associated solvents, propylene glycol (PG) and vegetable glycerin (VG). Here, we show that compared with smoke exposure, mice receiving ENDS vapor for 4 months failed to develop pulmonary inflammation or emphysema. However, ENDS exposure, independent of nicotine, altered lung lipid homeostasis in alveolar macrophages and epithelial cells. Comprehensive lipidomic and structural analyses of the lungs revealed aberrant phospholipids in alveolar macrophages and increased surfactant-associated phospholipids in the airway. In addition to ENDS-induced lipid deposition, chronic ENDS vapor exposure downregulated innate immunity against viral pathogens in resident macrophages. Moreover, independent of nicotine, ENDS-exposed mice infected with influenza demonstrated enhanced lung inflammation and tissue damage. Together, our findings reveal that chronic e-cigarette vapor aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. Notably, alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the vehicle solvents used in e-cigarettes.
Climate change is affecting biodiversity, but proximate drivers remain poorly understood. Here, we examine how experimental heatwaves impact on reproduction in an insect system. Male sensitivity to ...heat is recognised in endotherms, but ectotherms have received limited attention, despite comprising most of biodiversity and being more influenced by temperature variation. Using a flour beetle model system, we find that heatwave conditions (5 to 7 °C above optimum for 5 days) damaged male, but not female, reproduction. Heatwaves reduce male fertility and sperm competitiveness, and successive heatwaves almost sterilise males. Heatwaves reduce sperm production, viability, and migration through the female. Inseminated sperm in female storage are also damaged by heatwaves. Finally, we discover transgenerational impacts, with reduced reproductive potential and lifespan of offspring when fathered by males, or sperm, that had experienced heatwaves. This male reproductive damage under heatwave conditions provides one potential driver behind biodiversity declines and contractions through global warming.
Non-specific symptoms, as well as the lack of a cost-effective test to triage patients in primary care, has resulted in increased time-to-diagnosis and a poor prognosis for brain cancer patients. A ...rapid, cost-effective, triage test could significantly improve this patient pathway. A blood test using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy for the detection of brain cancer, alongside machine learning technology, is advancing towards clinical translation. However, whilst the methodology is simple and does not require extensive sample preparation, the throughput of such an approach is limited. Here we describe the development of instrumentation for the analysis of serum that is able to differentiate cancer and control patients at a sensitivity and specificity of 93.2% and 92.8%. Furthermore, preliminary data from the first prospective clinical validation study of its kind are presented, demonstrating how this innovative technology can triage patients and allow rapid access to imaging.
Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic ...senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.
The extent of SARS-CoV-2 infection throughout the United States population is currently unknown. High quality serology is key to avoiding medically costly diagnostic errors, as well as to assuring ...properly informed public health decisions. Here, we present an optimized ELISA-based serology protocol, from antigen production to data analyses, that helps define thresholds for IgG and IgM seropositivity with high specificities. Validation of this protocol is performed using traditionally collected serum as well as dried blood on mail-in blood sampling kits. Archival (pre-2019) samples are used as negative controls, and convalescent, PCR-diagnosed COVID-19 patient samples serve as positive controls. Using this protocol, minimal cross-reactivity is observed for the spike proteins of MERS, SARS1, OC43 and HKU1 viruses, and no cross reactivity is observed with anti-influenza A H1N1 HAI. Our protocol may thus help provide standardized, population-based data on the extent of SARS-CoV-2 seropositivity, immunity and infection.
PDF
