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Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca 2+ -dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans . These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders. Activation of autophagy, via the transcription factor TFEB, is a promising strategy to treat metabolic diseases. Here, the authors report three novel classes of small molecules that promote TFEB nuclear translocation, and provide evidence for the therapeutic efficacy of these compounds in mice and worms.

Numerous management strategies are implemented for the improvement in urban air quality worldwide, including control at tailpipe emissions. Control at the source is one of the best practices for pollution control, but this approach needs very stringent enforcement, public support, and monitoring for implementation. Besides, scientific processes-based technology to remove the pollutants from the ambient environment is also one of the approaches to improve air quality; however, high efficiency of such devices is one of the major challenges for the researchers. The present article is an attempt to review the state-of-the-art literature on such science-based technologies used to remove the pollutants from the ambient environment. The article highlighted the issues of high spatiotemporal variations in air pollution level in urban areas and methodologies available for the removal of pollutants. The efficiency of developed prototypes/devices using these processes is also compared worldwide. The technologies are available for particulate matter, and/or for gaseous pollutants. The air purification devices are designed and developed using scientific principles of bio-filtration, ionization, phytoremediation, photo-catalytic, and physical filtration. Based on the literature, it is found that ionization and physical filtration can remove particulate matter in the range of 61–95% and ~ 70%, respectively, while phytoremediation can remove in the range of 24–40%. The phytoremediation can remove NOx in the range of 10–15%. The efficiency of devices varies as pollution load and particle size distribution pattern varies. It is suggested that such control devices would be very useful in the reduction in air pollution at the hot spot area having high spatiotemporal variations.Graphic abstract

The emergence of COVID-19 put pressure on the Governments of most of the countries in the world to enforce nationwide lockdown (restriction of all non-essential activities) to curtail the spread of infection. The nationwide lockdown created an adverse impact on the economies around the world and altered the day-to-day life of people. The restrictions on pollution generating activities during the lockdown period resulted in an overall improvement of the air quality throughout the world including India. This study evaluated the impact on air quality in 46 cities throughout India and the findings indicate that on average, PM 2.5 and NO x , concentrations reduced by about 34% and 60%, respectively at different locations in India. PM 2.5 concentrations reduced by about 23%, 16%, 32%, and 28% in small, medium, large and megacities, respectively. However, the reduction in NO x concentrations was dissimilar to PM 2.5 in these cities. The findings further suggested that the impact of lockdown on air quality was not homogenous across the country and was probably due to varying background contributions. The average concentrations of PM 2.5 and NO x at background stations were found higher in large and mega cities than the smaller cities. The PM 2.5 concentrations at background stations were higher in North India in comparison to other parts of India.

CRISPR/Cas9 is an enabling RNA-guided technology for genome targeting and engineering. An acute DNA binding constraint of the Cas9 protein is the Protospacer Adjacent Motif (PAM). Here we demonstrate that the PAM requirement can be exploited to specifically target single-nucleotide heterozygous mutations while exerting no aberrant effects on the wild-type alleles. Specifically, we target the heterozygous G13A activating mutation of KRAS in colorectal cancer cells and we show reversal of drug resistance to a MEK small-molecule inhibitor. Our study introduces a new paradigm in genome editing and therapeutic targeting via the use of gRNA to guide Cas9 to a desired protospacer adjacent motif.

The originally published version of this Article contained an error in the spelling of the author Nathaniel W. Oswald, which was incorrectly given as Nathaniel W. Olswald. This has now been corrected in both the PDF and HTML versions of the Article.

Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.

A multi-genomic approach identifies the addiction of KRAS -mutant lung cancer cells to XPO1-dependent nuclear export, offering a new therapeutic opportunity. Druggable targets in KRAS-driven tumours These authors use RNA interference screening of more than a hundred human non-small-cell lung cancer cell lines to identify phenotypic variations selectively required for the survival of cells carrying mutations in the KRAS gene. They find that KRAS-driven cancers are dependent on the nuclear export machinery. This vulnerability can be exploited by clinically available drugs targeting nuclear export receptor XPO-1, which inhibit tumour growth at least in part by promoting nuclear accumulation of NF-κB inhibitors. Conversely, some KRAS-driven tumours bypass this dependence through co-occurring mutations that result in YAP1 activation. This resistance mechanism can be countered by coadministration of the YAP1/TEAD inhibitor verteporfin. The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity 1 . However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS -mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS -mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo . The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5–Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS -mutant lung cancers, and can be overcome with the co-administration of a YAP1–TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.

The role of the tumor immune microenvironment (TIME) in modulating responses to antiestrogen therapy in hormone receptor-positive (HR·) breast cancers remains unclear. We analyzed pre- and on-treatment biopsies from patients with HR· breast cancer treated with letrozole to induce estrogen deprivation (ED). Stromal tumor-infiltrating lymphocytes, assessed by H&E staining, and immune-related gene sets, including IFN-y signaling genes, measured by RNA-Seq, were increased in ED-resistant tumors. Cyclic immunofluorescence and spatial transcriptomics revealed an abundance of CD8· T cells and enhanced antigen processing and immune gene signatures in ED-resistant tumors. In this group, the expression of CXCL9, CXCL10, and CXCL11 - chemokine genes involved in CD8· T cell recruitment - and the CXCR3 receptor were upregulated both before and after letrozole treatment. CXCL11 levels were higher in conditioned media from HR· breast cancer cells cocultured with CD8· T cells. Both recombinant CXCL11 and coculture with CD8· T cells promoted MCF7 and T47D cell growth in estrogen-free conditions. Finally, deletion combined with silencing of the CXCL11 receptors CXCR3 and CXCR7 in MCF7 cells impaired proliferation in response to exogenous CXCL11 and to coculture with CD8· T cells in estrogen-free conditions. These findings suggest that CD8· T cell-associated CXCL11 in the TIME modulated the response of HR· breast cancer cells to estrogen suppression.

The role of the tumor immune microenvironment (TIME) in modulating responses to antiestrogen therapy in hormone receptor–positive (HR + ) breast cancers remains unclear. We analyzed pre- and on-treatment biopsies from patients with HR + breast cancer treated with letrozole to induce estrogen deprivation (ED). Stromal tumor–infiltrating lymphocytes, assessed by H&E staining, and immune-related gene sets, including IFN-γ signaling genes, measured by RNA-Seq, were increased in ED-resistant tumors. Cyclic immunofluorescence and spatial transcriptomics revealed an abundance of CD8 + T cells and enhanced antigen processing and immune gene signatures in ED-resistant tumors. In this group, the expression of CXCL9 , CXCL10 , and CXCL11 — chemokine genes involved in CD8 + T cell recruitment — and the CXCR3 receptor were upregulated both before and after letrozole treatment. CXCL11 levels were higher in conditioned media from HR + breast cancer cells cocultured with CD8 + T cells. Both recombinant CXCL11 and coculture with CD8 + T cells promoted MCF7 and T47D cell growth in estrogen-free conditions. Finally, deletion combined with silencing of the CXCL11 receptors CXCR3 and CXCR7 in MCF7 cells impaired proliferation in response to exogenous CXCL11 and to coculture with CD8 + T cells in estrogen-free conditions. These findings suggest that CD8 + T cell–associated CXCL11 in the TIME modulated the response of HR + breast cancer cells to estrogen suppression.

CRISPR/Cas9 is an enabling RNA-guided technology for genome targeting and engineering. An acute DNA binding constraint of the Cas9 protein is the Protospacer Adjacent Motif (PAM). Here we demonstrate that the PAM requirement can be exploited to specifically target single-nucleotide heterozygous mutations while exerting no aberrant effects on the wild-type alleles. Specifically, we target the heterozygous G13A activating mutation of KRAS in colorectal cancer cells and we show reversal of drug resistance to a MEK small-molecule inhibitor. Our study introduces a new paradigm in genome editing and therapeutic targeting via the use of gRNA to guide Cas9 to a desired protospacer adjacent motif.