Terpenoid Hydrazones as Biomembrane Penetration Enhancers: FT-IR Spectroscopy and Fluorescence Probe Studies

Hydrazones based on mono- and bicyclic terpenoids (verbenone, menthone and carvone) have been investigated in vitro as potential biomembrane penetration enhancers. In this regard, liposomes composed of lecithin or cardiolipin as phospholipid phase components with incorporated fluorescence probes have been prepared using the thin-film ultrasonic dispersion method. The mean particle size of the obtained liposomes, established using laser diffraction, was found to be 583 ± 0.95 nm, allowing us to categorize them as multilamellar vesicles (MLVs) according to their morphology. Pursuant to fluorescence analysis, we may assume a reduction in microviscosity and, consequently, a decrease in the packing density of lecithin and cardiolipin lipids to be the major mechanism of action for terpenoid hydrazones 1–15. In order to determine the molecular organization of the lipid matrix, lipids were isolated from rat strata cornea (SCs) and their interaction with tested compounds was studied by means of Fourier transform infrared spectroscopy. FT-IR examination suggested that these hydrazones fluidized the SC lipids via the disruption of the hydrogen-bonded network formed by polar groups of SC constituents. The relationship between the structure of terpenoid hydrazones and their ability to enhance biomembrane penetration is discussed.

Effects of homoeologous exchange on gene expression and alternative splicing in a newly formed allotetraploid wheat

Homoeologous exchange (HE) is a major mechanism generating post-polyploidization genetic variation with important evolutionary consequences. However, the direct impacts of HE without entangling with additional evolutionary forces on gene expression remains to be fully understood. Here, we analyzed high-throughput RNA-seq data of young leaves from individuals of a synthetic allotetraploid wheat (AADD), which contain variable numbers of HEs. We aimed to investigate if and to which extent HE directly impacts gene expression and alternative splicing (AS). We found that HE impacts expression of genes located within HE regions primarily via cis-acting dosage effect, which led to significant changes in the total expression of homoeolog pairs, especially for homoeologs whose original expression was biased. In parallel, HE influences expression of a large amount of genes residing in non-HE regions by trans-regulation leading to convergent expression of homoeolog pairs. Intriguingly, when taking into account of the original relative homoeolog expression states, homoeolog pairs under trans-effect are more prone to showing convergent response to HE whereas those under cis-effect trended to show subgenome-specific expression. Moreover, HE induced quantitative, largely individual-specific, changes of alternative splicing (AS) events. Like homoeologs expression, homoeo-AS events which related to trans effect were more responsive to HE. HE therefore exerts multifaceted immediate effects on gene expression and, to a less extent, also transcript diversity in nascent allopolyploidy.

An Intercellular Flow of Glutathione Regulated by Interleukin 6 Links Astrocytes and the Liver in the Pathophysiology of Amyotrophic Lateral Sclerosis

Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage.

WILD-seq: Clonal deconvolution of transcriptomic signatures of sensitivity and resistance to cancer therapeutics in vivo.

Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here we present WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, a platform that leverages expressed barcodes to simultaneously map clonal identities and transcriptional states at single cell resolution. Our optimised pipeline ensures recurrent representation of clonal lineages across animals and samples, facilitating analysis of clonal dynamics under perturbation. Application of WILD-seq to two triple negative mammary carcinoma mouse models, identified changes in clonal abundance, gene expression and microenvironment in response to JQ1 or taxane chemotherapy. WILD-seq reveals oxidative stress protection as a major mechanism of taxane resistance that renders our tumour models collaterally sensitive to non-essential amino acid deprivation. In summary, WILD-seq enables facile coupling of lineage and gene expression in vivo to elucidate clone-specific pathways of resistance to cancer therapies.

Molecular Mechanisms of Neurotransmitter Release Control Distinct Features of Sensory Coding Reliability

A key requirement for the repeated identification of a stimulus is a reliable neural representation each time it is encountered. Neural coding is often considered to rely on two major coding schemes: the firing rate of action potentials, known as rate coding, and the precise timing of action potentials, known as temporal coding. Synaptic transmission is the major mechanism of information transfer between neurons. While theoretical studies have examined the effects of neurotransmitter release probability on neural code reliability, it has not yet been addressed how different components of the release machinery affect coding of physiological stimuli in vivo. Here, we use the first synapse of the Drosophila olfactory system to show that the reliability of the neural code is sensitive to perturbations of specific presynaptic proteins controlling distinct stages of neurotransmitter release. Notably, the presynaptic manipulations decreased coding reliability of postsynaptic neurons only at high odor intensity. We further show that while the reduced temporal code reliability arises from monosynaptic effects, the reduced rate code reliability arises from circuit effects, which include the recruitment of inhibitory local neurons. Finally, we find that reducing neural coding reliability decreases behavioral reliability of olfactory stimulus classification.

Mechanisms of FA-Phagy, a New Form of Selective Autophagy/Organellophagy

Focal adhesions (FAs) are adhesive organelles that attach cells to the extracellular matrix and can mediate various biological functions in response to different environmental cues. Reduced FAs are often associated with enhanced cell migration and cancer metastasis. In addition, because FAs are essential for preserving vascular integrity, the loss of FAs leads to hemorrhages and is frequently observed in many vascular diseases such as intracranial aneurysms. For these reasons, FAs are an attractive therapeutic target for treating cancer or vascular diseases, two leading causes of death world-wide. FAs are controlled by both their formation and turnover. In comparison to the large body of literature detailing FA formation, the mechanisms of FA turnover are poorly understood. Recently, autophagy has emerged as a major mechanism to degrade FAs and stabilizing FAs by inhibiting autophagy has a beneficial effect on breast cancer metastasis, suggesting autophagy-mediated FA turnover is a promising drug target. Intriguingly, autophagy-mediated FA turnover is a selective process and the cargo receptors for recognizing FAs in this process are context-dependent, which ensures the degradation of specific cargo. This paper mainly reviews the cargo recognition mechanisms of FA-phagy (selective autophagy-mediated FA turnover) and its disease relevance. We seek to outline some new points of understanding that will facilitate further study of FA-phagy and precise therapeutic strategies for related diseases associated with aberrant FA functions.

COP1 promotes seed germination by destabilizing RGA-LIKE2 (RGL2) in Arabidopsis

Under favorable moisture, temperature and light conditions, gibberellin (GA) biosynthesis is induced and triggers seed germination. A major mechanism by which GA promotes seed germination is by promoting the degradation of the DELLA protein RGL2, a major repressor of germination in Arabidopsis seeds. Analysis of seed germination phenotypes of constitutively photomorphogenic 1 (cop1) mutants and complemented COP1-OX/cop1-4 lines in response to GA and paclobutrazol (PAC) suggested a positive role for COP1 in seed germination and a relation with GA signaling. cop1-4 mutant seeds showed PAC hypersensitivity, but transformation with a COP1 overexpression construct rendered them PAC insensitive, with a phenotype similar to that of rgl2 mutant (rgl2-SK54) seeds. Furthermore, cop1-4 rgl2-SK54 double mutants showed a PAC-insensitive germination phenotype like that of rgl2-SK54, identifying COP1 as an upstream negative regulator of RGL2. COP1 interacts directly with RGL2 and in vivo this interaction is strongly enhanced by SPA1. COP1 directly ubiquitinates RGL2 to promote its degradation. Moreover, GA stabilizes COP1 with consequent RGL2 destabilization. By uncovering this COP1-RGL2 regulatory module, we reveal a novel mechanism whereby COP1 positively regulates seed germination and controls the expression of germination-promoting genes.

Sensitivity of SARS-CoV-2 towards Alcohols: Potential for Alcohol-Related Toxicity in Humans

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative organism that is highly contagious and has been responsible for more than 240 million cases and 5 million deaths worldwide. Using masks, soap-based hand washing, and maintaining social distancing are some of the common methods to prevent the spread of the virus. In the absence of any preventive medications, from the outset of pandemic, alcohol-based hand sanitizers (ABHS) have been one of the first-line measures to control transmission of Coronavirus Disease 2019 (COVID-19). The purpose of this narrative review is to evaluate the sensitivity of SARS-CoV-2 towards ABHS and understand their potential adverse effects on humans. Ethanol and isopropanol have been the most commonly used alcohols in ABHS (e.g., gel, solution, spray, wipes, or foam) with alcohol in the range of 70–85% v/v in World Health Organization or Food and Drug Administration-approved ABHS. The denaturation of proteins around the envelope of SARS-CoV-2 positive sense single-stranded RNA virus is the major mechanism of action of ABHS. Due to frequent use of high-percentage alcohol-containing ABHS over an extended period of time, the oral, dermal, or pulmonary absorption is a possibility. In addition to the systemic toxicity, topical adverse effects such as contact dermatitis and atopic dermatitis are plausible and have been reported during COVID-19. ABHS appear to be effective in controlling the transmission of SARS-CoV-2 with the concern of oral, dermal, or pulmonary absorption.

Differentiation therapy for myeloid malignancies: beyond cytotoxicity

Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.

Multiphase Outflows in High-redshift Quasar Host Galaxies

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of six radio-loud quasar host galaxies at z = 1.4–2.3. We combine the kiloparsec-scale resolution ALMA observations with high spatial resolution adaptive optics integral field spectrograph data of the ionized gas. We detect molecular gas emission in five quasar host galaxies and resolve the molecular interstellar medium using the CO (3–2) or CO (4–3) rotational transitions. Clumpy molecular outflows are detected in four quasar host galaxies and a merger system 21 kpc away from one quasar. Between the ionized and cold molecular gas phases, the majority of the outflowing mass is in a molecular phase, while for three out of four detected multiphase gas outflows, the majority of the kinetic luminosity and momentum flux is in the ionized phase. Combining the energetics of the multiphase outflows, we find that their driving mechanism is consistent with energy-conserving shocks produced by the impact of the quasar jets with the gas in the galaxy. By assessing the molecular gas mass to the dynamics of the outflows, we estimate a molecular gas depletion timescale of a few megayears. The gas outflow rates exceed the star formation rates, suggesting that quasar feedback is a major mechanism of gas depletion at the present time. The coupling efficiency between the kinetic luminosity of the outflows and the bolometric luminosity of the quasar of 0.1%–1% is consistent with theoretical predictions. Studying multiphase gas outflows at high redshift is important for quantifying the impact of negative feedback in shaping the evolution of massive galaxies.