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Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin 1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19. In late 2019, a new virus named SARS-CoV-2, which causes a disease in humans called COVID-19, emerged in China and quickly spread around the world. Many individuals infected with the virus develop only mild, symptoms including a cough, high temperature and loss of sense of smell; while others may develop no symptoms at all. However, some individuals develop much more severe, life-threatening symptoms affecting the lungs and other parts of the body including the heart and brain. SARS-CoV-2 uses a human enzyme called ACE2 like a ‘Trojan Horse’ to sneak into the cells of its host. ACE2 lowers blood pressure in the human body and works against another enzyme known as ACE (which has the opposite effect). Therefore, the body has to balance the levels of ACE and ACE2 to maintain a normal blood pressure. It remains unclear whether SARS-CoV-2 affects how ACE2 and ACE work. When COVID-19 first emerged, a team of researchers in China studied fluid and cells collected from the lungs of patients to help them identify the SARS-CoV-2 virus. Here, Garvin et al. analyzed the data collected in the previous work to investigate whether changes in how the body regulates blood pressure may contribute to the life-threatening symptoms of COVID-19. The analyses found that SARS-CoV-2 caused the levels of ACE in the lung cells to decrease, while the levels of ACE2 increased. This in turn increased the levels of a molecule known as bradykinin in the cells (referred to as a ‘Bradykinin Storm’). . Previous studies have shown that bradykinin induces pain and causes blood vessels to expand and become leaky which will lead to swelling and inflammation of the surrounding tissue. In addition, the analyses found that production of a substance called hyaluronic acid was increased and the enzymes that could degrade it greatly decreased. Hyaluronic acid can absorb more than 1,000 times its own weight in water to form a hydrogel. The Bradykinin-Storm-induced leakage of fluid into the lungs combined with the excess hyaluronic acid would likely result in a Jello-like substance that is preventing oxygen uptake and carbon dioxide release in the lungs of severely affected COVID-19 patients. Therefore, the findings of Garvin et al. suggest that the Bradykinin Storm may be responsible for the more severe symptoms of COVID-19. Further experiments identified several existing medicinal drugs that have the potential to be re-purposed to treat the Bradykinin Storm. A possible next step would be to carry out clinical trials to assess how effective these drugs are in treating patients with COVID-19. In addition, understanding how SARS-Cov-2 affects the body will help researchers and clinicians identify individuals who are most at risk of developing life-threatening symptoms.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous neuropsychiatric condition whose cause is still unknown. A common function of proteins encoded by reported risk-genes for ASD is chromatin modification, but how this biological process relates to neurodevelopment and autism is unknown. We recently reported frequent genomic variants displaying Non-Mendelian inheritance (NMI) patterns in family trios in two cohorts of individuals with autism. These loci represent putative structural variants (SV) and the genes that carry them participate in neurodevelopment, glutamate signaling, and chromatin modification, confirming previous reports and providing greater detail for involvement of these processes in ASD. The majority of these loci were found in non-coding regions of the genome and were enriched for expression quantitative trait loci suggesting that gene dysregulation results from these genomic disruptions rather than alteration of proteins. Here, we intersected these putative ASD-associated SVs from our earlier work with diverse genome-wide gene regulatory and epigenetic multi-omic layers to identify statistically significant enrichments to understand how they may function to produce autism. We find that these loci are enriched in dense heterochromatin and in transcription factor binding sites for SATB1, SRSF9, and NUP98-HOXA9. A model based on our results indicates that the core of ASD may reside in the dysregulation of a process analogous to RNA-induced Initiation of Transcriptional gene silencing that is meant to maintain heterochromatin. This produces SVs in the genes within these chromosomal regions, which also happen to be enriched for those involved in brain development and immune response. This study mechanistically links previously reported ASD-risk genes involved in chromatin remodeling with neurodevelopment and may explain the role of mutations in ASD. Our results suggest that a large portion of the heritable component of autism is the result of changes in genes that control critical epigenetic processes.

Background A mechanistic understanding of the spread of SARS-CoV-2 and diligent tracking of ongoing mutagenesis are of key importance to plan robust strategies for confining its transmission. Large numbers of available sequences and their dates of transmission provide an unprecedented opportunity to analyze evolutionary adaptation in novel ways. Addition of high-resolution structural information can reveal the functional basis of these processes at the molecular level. Integrated systems biology-directed analyses of these data layers afford valuable insights to build a global understanding of the COVID-19 pandemic. Results Here we identify globally distributed haplotypes from 15,789 SARS-CoV-2 genomes and model their success based on their duration, dispersal, and frequency in the host population. Our models identify mutations that are likely compensatory adaptive changes that allowed for rapid expansion of the virus. Functional predictions from structural analyses indicate that, contrary to previous reports, the Asp 614 Gly mutation in the spike glycoprotein (S) likely reduced transmission and the subsequent Pro 323 Leu mutation in the RNA-dependent RNA polymerase led to the precipitous spread of the virus. Our model also suggests that two mutations in the nsp13 helicase allowed for the adaptation of the virus to the Pacific Northwest of the USA. Finally, our explainable artificial intelligence algorithm identified a mutational hotspot in the sequence of S that also displays a signature of positive selection and may have implications for tissue or cell-specific expression of the virus. Conclusions These results provide valuable insights for the development of drugs and surveillance strategies to combat the current and future pandemics.

Extensive fibrin deposition in the lungs and altered levels of circulating blood coagulation proteins in COVID-19 patients imply local derangement of pathways that limit fibrin formation and/or promote its clearance. We examined transcriptional profiles of bronchoalveolar lavage fluid (BALF) samples to identify molecular mechanisms underlying these coagulopathies. mRNA levels for regulators of the kallikrein–kinin (C1-inhibitor), coagulation (thrombomodulin, endothelial protein C receptor), and fibrinolytic (urokinase and urokinase receptor) pathways were significantly reduced in COVID-19 patients. While transcripts for several coagulation proteins were increased, those encoding tissue factor, the protein that initiates coagulation and whose expression is frequently increased in inflammatory disorders, were not increased in BALF from COVID-19 patients. Our analysis implicates enhanced propagation of coagulation and decreased fibrinolysis as drivers of the coagulopathy in the lungs of COVID-19 patients.

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.50 Å resolution crystal structure of 3CLpro C145S bound to NEMO 226–234 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro-NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for, in the pathology of COVID-19. The authors report crystallographic and computational studies that detail how SARS-CoV-2 3CLpro cleaves the host NF-κB Essential Modulator in addition to its canonical viral substrates. The association with the high fitness of SARS-CoV-2 in humans is discussed.

Diet may be modified seasonally or by biogeographic, demographic or cultural shifts. It can differentially influence mitochondrial bioenergetics, retrograde signalling to the nuclear genome, and anterograde signalling to mitochondria. All these interactions have the potential to alter the frequencies of mtDNA haplotypes (mitotypes) in nature and may impact human health. In a model laboratory system, we fed four diets varying in Protein: Carbohydrate (P:C) ratio (1:2, 1:4, 1:8 and 1:16 P:C) to four homoplasmic Drosophila melanogaster mitotypes (nuclear genome standardised) and assayed their frequency in population cages. When fed a high protein 1:2 P:C diet, the frequency of flies harbouring Alstonville mtDNA increased. In contrast, when fed the high carbohydrate 1:16 P:C food the incidence of flies harbouring Dahomey mtDNA increased. This result, driven by differences in larval development, was generalisable to the replacement of the laboratory diet with fruits having high and low P:C ratios, perturbation of the nuclear genome and changes to the microbiome. Structural modelling and cellular assays suggested a V161L mutation in the ND4 subunit of complex I of Dahomey mtDNA was mildly deleterious, reduced mitochondrial functions, increased oxidative stress and resulted in an increase in larval development time on the 1:2 P:C diet. The 1:16 P:C diet triggered a cascade of changes in both mitotypes. In Dahomey larvae, increased feeding fuelled increased β-oxidation and the partial bypass of the complex I mutation. Conversely, Alstonville larvae upregulated genes involved with oxidative phosphorylation, increased glycogen metabolism and they were more physically active. We hypothesise that the increased physical activity diverted energy from growth and cell division and thereby slowed development. These data further question the use of mtDNA as an assumed neutral marker in evolutionary and population genetic studies. Moreover, if humans respond similarly, we posit that individuals with specific mtDNA variations may differentially metabolise carbohydrates, which has implications for a variety of diseases including cardiovascular disease, obesity, and perhaps Parkinson's Disease.

Here we determine the sex-specific influence of mtDNA type (mitotype) and diet on mitochondrial functions and physiology in two Drosophila melanogaster lines. In many species, males and females differ in aspects of their energy production. These sex-specific influences may be caused by differences in evolutionary history and physiological functions. We predicted the influence of mtDNA mutations should be stronger in males than females as a result of the organelle's maternal mode of inheritance in the majority of metazoans. In contrast, we predicted the influence of diet would be greater in females due to higher metabolic flexibility. We included four diets that differed in their protein: carbohydrate (P:C) ratios as they are the two-major energy-yielding macronutrients in the fly diet. We assayed four mitochondrial function traits (Complex I oxidative phosphorylation, reactive oxygen species production, superoxide dismutase activity, and mtDNA copy number) and four physiological traits (fecundity, longevity, lipid content, and starvation resistance). Traits were assayed at 11 d and 25 d of age. Consistent with predictions we observe that the mitotype influenced males more than females supporting the hypothesis of a sex-specific selective sieve in the mitochondrial genome caused by the maternal inheritance of mitochondria. Also, consistent with predictions, we found that the diet influenced females more than males.

The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm.

A fundamental understanding of the underlying mechanisms involved in biological invasions is crucial to developing effective risk assessment and control measures against invasive species. The fall armyworm (FAW), Spodoptera frugiperda, is a highly invasive pest that has rapidly spread from its native Americas into much of the Eastern Hemisphere, with a highly homogeneous nuclear genetic background. However, the exact mechanism behind its rapid introduction and propagation remains unclear. Here, a systematic investigation is conducted into the population dynamics of FAW in China from 2019 to 2021 and found that FAW individuals carrying “rice” mitochondria (FAW‐mR) are more prevalent (>98%) than that with “corn” mitochondria (FAW‐mC) at the initial stage of the invasion and in newly‐occupied non‐overwintering areas. Further fitness experiments show that the two hybrid‐strains of FAW exhibit different adaptions in the new environment in China, and this may have been facilitated by amino acid changes in mitochondrial‐encoded proteins. FAW‐mR used increases energy metabolism, faster wing‐beat frequencies, and lower wing loadings to drive greater flight performance and subsequent rapid colonization of new habitats. In contrast, FAW‐mC individuals adapt with more relaxed mitochondria and shuttle energetics into maternal investment, observed as faster development rate and higher fecundity. The presence of two different mitochondria types within FAW has the potential to significantly expand the range of damage and enhance competitive advantage. Overall, the study describes a novel invasion mechanism displayed by the FAW population that facilitates its expansion and establishment in new environments. Here, the study describes a novel invasion mechanism displayed by fall armyworm that facilitates its expansion and establishment in new environments. The rice strain used increases energy metabolism, faster wing‐beat frequencies, and lower wing loadings to drive greater flight performance, while corn stran adapts with more relaxed mitochondria and shuttle energetics into maternal investment, observed as faster development rate and higher fecundity.

Early in the SARS-CoV-2 pandemic, we compared transcriptome data from hospitalized COVID-19 patients and control patients without COVID-19. We found changes in procoagulant and fibrinolytic gene expression in the lungs of COVID-19 patients (Mast et al., 2021). These findings have been challenged based on issues with the samples (Fitzgerald and Jamieson, 2022). We have revisited our previous analyses in the light of this challenge and find that these new analyses support our original conclusions.