HSP60/10 chaperonin systems are inhibited by a variety of approved drugs,natural products,and known bioactive molecules

All living organisms contain a unique class of molecular chaperones called 60?kDa heat shock proteins (HSP60 – also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus – MRSA). Intriguingly, during our studies we found that three known antibiotics – suramin, closantel, and rafoxanide – were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.     

BOLD Granger Causality Reflects Vascular Anatomy

A number of studies have tried to exploit subtle phase differences in BOLD time series to resolve the order of sequential activation of brain regions, or more generally the ability of signal in one region to predict subsequent signal in another region. More recently, such lag-based measures have been applied to investigate directed functional connectivity, although this application has been controversial. We attempted to use large publicly available datasets (FCON 1000, ADHD 200, Human Connectome Project) to determine whether consistent spatial patterns of Granger Causality are observed in typical fMRI data. For BOLD datasets from 1,240 typically developing subjects ages 7–40, we measured Granger causality between time series for every pair of 7,266 spherical ROIs covering the gray matter and 264 seed ROIs at hubs of the brain’s functional network architecture. Granger causality estimates were strongly reproducible for connections in a test and replication sample (n=620 subjects for each group), as well as in data from a single subject scanned repeatedly, both during resting and passive video viewing. The same effect was even stronger in high temporal resolution fMRI data from the Human Connectome Project, and was observed independently in data collected during performance of 7 task paradigms. The spatial distribution of Granger causality reflected vascular anatomy with a progression from Granger causality sources, in Circle of Willis arterial inflow distributions, to sinks, near large venous vascular structures such as dural venous sinuses and at the periphery of the brain. Attempts to resolve BOLD phase differences with Granger causality should consider the possibility of reproducible vascular confounds, a problem that is independent of the known regional variability of the hemodynamic response.     

Community invasibility and invasion by non-native Fraxinus pennsylvanica trees in a degraded tropical forest

Whether invasion of introduced plant species may be aided by certain community properties is poorly understood for species-rich ecosystems, such as tropical montane forests. In Kenya, the non-native tree Fraxinus pennsylvanica has invaded degraded montane forests. We used generalized linear mixed models to examine the relative importance of different community properties to Fraxinus invasion after agricultural abandonment and in the secondary forest. Fraxinus invasion was positively related to plant community species diversity and the abundance of tree saplings, shrubs, ferns, and herbs in the abandoned fallows, but negatively related to the same community properties in the secondary forest. The number of Fraxinus recruits declined with declining propagule pressure in the fallows, but not in the secondary forest. Although adult and saplings of Fraxinus were positively related to community diversity in the fallows, Fraxinus appeared to decrease diversity in the secondary forest. These results show that the success of non-native species invasion and the effects of an invader on the resident community may depend both on properties and degree of disturbance of the community. Plant community diversity and evenness appeared to determine the invasion success by increasing invasibility of the abandoned fallows, but decreasing invasibility of the secondary forest. Our results from a tropical degraded forest emphasize the importance of including habitat characteristics when predicting both the potential of non-native plant invasion and effects of invasives on the particular community.     

Environmental resource deficit may drive the evolution of intraspecific trait variation in invasive plant populations

Intraspecific trait variation within natural populations (i.e. intra‐population trait variation, IPTV) is the basic source for selection and can have significant ecological consequences. Higher IPTV may increase a population's niche breath and benefit interspecies competition under a resource‐limited environment, thus affecting the ability of a species to move into novel habitats. However, the reciprocal influences of variation in environmental conditions and phenotypic trait expression in spreading plant populations are not clearly defined. We propose that during invasion, IPTV and its relative change in response to key resource enrichment may increase with the resource deficit of invaded sites, and that this relationship may facilitate plant invasions into resource‐limited environments. We analyzed the invasion trend, IPTV and its response to water enrichment, and moisture variability among populations of an annual grass Brachypodium hybridum in California, United States. We incorporated a genotyping‐by‐sequencing approach, a common garden experiment that had two water level treatments, and public plant and climate databases. Our hypothesis was supported by the observation that for populations that invaded sites with higher spring moisture deficit, both their seed biomass IPTV (for the water‐enriched treatment only) and relative change of the IPTV across water treatments were larger when examined in the common garden experiment. A generally north to south spreading direction was found in these B. hybridum populations, towards a drier and warmer climate exhibiting higher moisture deficit for plant growth. Our results suggest a role for interactions between IPTV (rather than trait means) and environmental resource availability in promoting plant invasions, providing new insights into the significance of IPTV in shaping plant geographic distributions.     

Focus: Vaccines: Myocarditis Following COVID-19 Vaccination: A Systematic Review of Case Reports

Introduction: COVID-19, the infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), often presents with a spectrum of symptoms at varying levels of severity, ranging from asymptomatic patients to those with fatal complications, such as myocarditis. With increased availability of COVID-19 vaccines, the awareness of possible side effects has expanded as reports surface. This study reviewed cases of myocarditis following COVID-19 vaccination and with existing literature on COVID-19 infection-induced myocarditis to compare clinical courses and analyze possible mechanisms of action. Methods: A systematic review of literature was conducted to identify published case reports (as of February 3, 2022) pertaining to the development of myocarditis following COVID-19 vaccination with either Pfizer or Moderna for an in-depth analysis. Additional subgroup analyses were conducted based on age, past medical history, vaccine manufacturer, and dose number. Results: There were 53 eligible case reports that were included in this study. Patients were mostly male with a median age of 24 years, and the most reported symptom upon presentation was chest pain. Seventy percent of the cases involved the Pfizer vaccine with a majority of myocarditis developing subsequent to second dose. Resolution of symptoms was achieved in all but one patient. Clinical severity, as measured primarily by left ventricular ejection fraction, appeared to be worse among adult patients than pediatric, as well as for patients with comorbidities. Conclusion: This study revealed an observable association between COVID-19 vaccines and myocarditis. However, the clinical course and prognosis seem favorable and less prevalent than those conferred from natural infection.     

Sit4p/PP6 regulates ER-to-Golgi traffic by controlling the dephosphorylation of COPII coat subunits

Traffic from the endoplasmic reticulum (ER) to the Golgi complex is initiated when the activated form of the GTPase Sar1p recruits the Sec23p-Sec24p complex to ER membranes. The Sec23p-Sec24p complex, which forms the inner shell of the COPII coat, sorts cargo into ER-derived vesicles. The coat inner shell recruits the Sec13p-Sec31p complex, leading to coat polymerization and vesicle budding. Recent studies revealed that the Sec23p subunit sequentially interacts with three different binding partners to direct a COPII vesicle to the Golgi. One of these binding partners is the serine/threonine kinase Hrr25p. Hrr25p phosphorylates the COPII coat, driving the membrane-bound pool into the cytosol. The phosphorylated coat cannot rebind to the ER to initiate a new round of vesicle budding unless it is dephosphorylated. Here we screen all known protein phosphatases in yeast to identify one whose loss of function alters the cellular distribution of COPII coat subunits. This screen identifies the PP2A-like phosphatase Sit4p as a regulator of COPII coat dephosphorylation. Hyperphosphorylated coat subunits accumulate in the sit4Δ mutant in vivo. In vitro, Sit4p dephosphorylates COPII coat subunits. Consistent with a role in coat recycling, Sit4p and its mammalian orthologue, PP6, regulate traffic from the ER to the Golgi complex.