HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.

Mohamad Navab
Sep 1, 2000; 41:1495-1508
Articles

Mohamad Navab
Sep 1, 2000; 41:1481-1494
Articles

M. Mahmood Hussain
Jan 1, 2003; 44:22-32
Reviews

John M. Dietschy
Aug 1, 2004; 45:1375-1397
Thematic Reviews

JM Dietschy
Oct 1, 1993; 34:1637-1659
Reviews

Ronald M. Krauss
Jan 1, 1982; 23:97-104
Articles

Chatham House Prize: Malawi Judges Win for Election Work News Release NCapeling 23 October 2020

Malawi’s constitutional court judges have won the 2020 Chatham House Prize in recognition of their 'courage and independence in the defence of democracy'.

Digital governance must not marginalize smaller states Expert comment LToremark 19 May 2021

For effective and inclusive digital governance, multi-stakeholderism must raise its game.

Last month, the G7 announced it is to work towards a trusted, values-driven digital ecosystem. While this is commendable, the G7 must recognize that key international digital governance decisions should involve all states whose populations will be affected. Not doing so is to deny the legitimate interests of those populations and may cause a lack of trust in international digital governance that embeds longer-term instability.

While a multi-stakeholder approach to digital governance is important, it must be structured in a way that allows for meaningful representation of states’ interests and ensures their representatives have the opportunity and capacity to take part. As the internet becomes fundamental to life in every country of the world, international digital governance is increasingly important to all governments and excluding some states’ perspectives may engender wider risks to international security and governance.

The ‘glitter ball’ of digital governance

International digital governance is playing catch-up with the digital sphere it needs to govern. Its starting point is a ‘glitter ball’ of governance initiatives: a large number of complex facets with overlapping impacts – and an almost impenetrable core. Governance initiatives (see infographic) include governance of the internet itself and its uses, international cybersecurity, international human rights, data management, as well as the impact of digital developments in areas such as armed conflict, trade and health.

Many of the bodies involved – such as the Internet Governance Forum, the Internet Corporation for Assigned Names and Numbers (ICANN) and technical standards bodies – include a wide range of stakeholders, yet there is no one accessible, central body. Furthermore, certain key issues, such as the role and responsibilities of tech platforms, are barely touched upon by international governance mechanisms. There is also currently only a limited role for traditional UN multilateral decision-making, a process which builds in a role for smaller states.

The sheer number of forums involved, each with a different set of working methods and rules on participation, makes it difficult to fully grasp what digital governance looks like as a whole. The UN secretary-general’s High-level Panel on Digital Cooperation recognized the complexity of digital cooperation arrangements and the barriers to inclusion facing small and developing countries as well as under-represented groups. In response, the June 2020 UN Roadmap on Digital Cooperation accepts the need to streamline digital governance while ensuring marginalized voices are heard.

The UN is considering potential models for future governance, each of which would – reassuringly – involve multi-stakeholder participation, dedicated funds to boost participation, consolidation of discussions currently split between different forums and a minor coordinating role for the UN.  

Building in roles for smaller states

As the UN designs new digital governance architecture, it is particularly important to build in roles for small and medium states. Core constituencies affected by decisions should be at the centre and governments – as guardians of public interest – should have a key say in the decision-making process. The distrust generated by built-in power imbalances needs to be addressed, as does the dominance of voices from the Global North in bodies such as ICANN.   

There has been some progress made to increase participation. For example, the Freedom Online Coalition includes a number of developing countries and the 2020 Internet Governance Forum included input from 175 states.

However, participation is not only a matter of having a seat at the table. As discussed at the March 2021 UN Open-ended Working Group on ICTs in the context of international security, capacity-building is vital. The group’s conclusions include the suggested development of a global cyber capacity-building agenda with information sharing and norms guidance under the auspices of the UN. Representatives of small and medium states need a roadmap to understand in which forums they can defend and pursue their interests, and the financial help to do so if necessary.

Managing multi-stakeholder participation

A multi-stakeholder approach has been fundamental to digital governance from the start and has played a vital role in helping to secure the openness and universality of the internet. This approach is rightly seen as essential to effective governance because it introduces diverse expertise, allows the interests of all impacted sectors to be taken into account and helps ensure decisions are accepted by those affected.

However, as identified in a Chatham House report on inclusive global governance, multi-stakeholderism needs to raise its game. One of its downsides is that in the cacophony some important voices may not be heard because they lack resource or capacity to speak up. There is a perennial risk of debate and decision-making being captured by the wealthiest companies or the most powerful states. At present, small and medium states are under-represented in multi-stakeholder forums and it is important that those managing such forums seek to identify and include previously excluded voices.

Multi-stakeholderism should not come at the expense of efficiency. While it does not have to mean huge, inefficient meetings or endless discussion, it should also not mean that smaller, less well-funded voices are not heard. Instead, such processes should enable representation of appropriate interest groups, complemented by wider meetings (such as regional meetings, or sector-specific meetings) as needed. While inclusivity and transparency are key, synergies between regional and global forums can work well –  for example, some countries have adopted national versions of the Internet Governance Forum –  and so too can hybrid models such as the Freedom Online Coalition, which meets both as government members and for regular multi-stakeholder dialogue.

A multi-stakeholder approach should also not lose sight of the key role of states – and where mandated, sub-state entities – in making public policy decisions.

An important role for the UN

For 75 years, the UN has acted as a bulwark of international security and shared values, and a promoter of economic and social development. If misused, technology has the potential to undermine this bulwark, to facilitate conflict, erode rights and undermine development. The UN must encourage the harnessing of technology for society’s benefit, while leading a collective effort to guard against the risks through the retention and growth of a universal, open internet – particularly in the face of growing digital authoritarianism exacerbated by COVID-19.

The UN can also help protect against a commercial culture that threatens to trample fundamental freedoms of privacy and autonomy in its pursuit of wealth and to widen economic and social gulfs by leaving large swathes of the world behind. If the UN is to play this role effectively – and for the benefit of all its members ­– it requires the active participation of all states, large and small.

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

Expert

Soun-Hi Kwon
Trans. Amer. Math. Soc. 377 (), 6021-6022.
Abstract, references and article information

Carolyn S. Gordon and Michael R. Jablonski
Trans. Amer. Math. Soc. 377 (), 5673-5704.
Abstract, references and article information

Noga Alon, Anurag Bishnoi, Shagnik Das and Alessandro Neri
Trans. Amer. Math. Soc. 377 (), 5389-5410.
Abstract, references and article information

Denise Uwamariya and Xiangfeng Yang
Theor. Probability and Math. Statist. 111 (), 167-179.
Abstract, references and article information

Olha Prykhodko and Kostiantyn Ralchenko
Theor. Probability and Math. Statist. 111 (), 123-135.
Abstract, references and article information

Lutz Mattner
Theor. Probability and Math. Statist. 111 (), 45-122.
Abstract, references and article information

Paweł Hitczenko and Nick Wormald
Proc. Amer. Math. Soc. 152 (), 5411-5427.
Abstract, references and article information

Shengyu Tang
Proc. Amer. Math. Soc. 152 (), 5381-5394.
Abstract, references and article information

Donghyeok Lim and Christian Maire
Proc. Amer. Math. Soc. 152 (), 5013-5024.
Abstract, references and article information

Anton Freund, Fedor Pakhomov and Giovanni Soldà
Proc. Amer. Math. Soc. 152 (), 4993-5005.
Abstract, references and article information

Yu. L. Ershov
St. Petersburg Math. J. 35 (), 461-465.
Abstract, references and article information

Zhanqiang Bai, Jia-Jun Ma, Wei Xiao and Xun Xie
Represent. Theory 28 (), 498-513.
Abstract, references and article information

Reliable, specific polyclonal and monoclonal antibodies are important tools in research and medicine. However, the discovery of antibodies against their targets in their native forms is difficult. Here, we present a novel method for discovery of antibodies against membrane proteins in their native configuration in mammalian cells. The method involves the co-expression of an antibody library in a population of mammalian cells that express the target polypeptide within a natural membrane environment on the cell surface. Cells that secrete a single-chain fragment variable (scFv) that binds to the target membrane protein thereby become self-labeled, enabling enrichment and isolation by magnetic sorting and FRET-based flow sorting. Library sizes of up to 109 variants can be screened, thus allowing campaigns of naïve scFv libraries to be selected against membrane protein antigens in a Chinese hamster ovary cell system. We validate this method by screening a synthetic naïve human scFv library against Chinese hamster ovary cells expressing the oncogenic target epithelial cell adhesion molecule and identify a panel of three novel binders to this membrane protein, one with a dissociation constant (KD) as low as 0.8 nm. We further demonstrate that the identified antibodies have utility for killing epithelial cell adhesion molecule–positive cells when used as a targeting domain on chimeric antigen receptor T cells. Thus, we provide a new tool for identifying novel antibodies that act against membrane proteins, which could catalyze the discovery of new candidates for antibody-based therapies.

Carnosine (β-alanyl-l-histidine) and anserine (β-alanyl-3-methyl-l-histidine) are abundant peptides in the nervous system and skeletal muscle of many vertebrates. Many in vitro and in vivo studies demonstrated that exogenously added carnosine can improve muscle contraction, has antioxidant activity, and can quench various reactive aldehydes. Some of these functions likely contribute to the proposed anti-aging activity of carnosine. However, the physiological role of carnosine and related histidine-containing dipeptides (HCDs) is not clear. In this study, we generated a mouse line deficient in carnosine synthase (Carns1). HCDs were undetectable in the primary olfactory system and skeletal muscle of Carns1-deficient mice. Skeletal muscle contraction in these mice, however, was unaltered, and there was no evidence for reduced pH-buffering capacity in the skeletal muscle. Olfactory tests did not reveal any deterioration in 8-month-old mice lacking carnosine. In contrast, aging (18–24-month-old) Carns1-deficient mice exhibited olfactory sensitivity impairments that correlated with an age-dependent reduction in the number of olfactory receptor neurons. Whereas we found no evidence for elevated levels of lipoxidation and glycation end products in the primary olfactory system, protein carbonylation was increased in the olfactory bulb of aged Carns1-deficient mice. Taken together, these results suggest that carnosine in the olfactory system is not essential for information processing in the olfactory signaling pathway but does have a role in the long-term protection of olfactory receptor neurons, possibly through its antioxidant activity.

VAR2CSA is the placental-malaria–specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.

Abnormal changes of neuronal Tau protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer's disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remain ill-defined. Tau contains ∼85 potential phosphorylation sites, which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, methodological limitations (e.g. in MS of phosphopeptides, or antibodies against phosphoepitopes) led to conflicting results regarding the extent of Tau phosphorylation in cells. Here we present results from a new approach based on native MS of intact Tau expressed in eukaryotic cells (Sf9). The extent of phosphorylation is heterogeneous, up to ∼20 phosphates per molecule distributed over 51 sites. The medium phosphorylated fraction Pm showed overall occupancies of ∼8 Pi (± 5) with a bell-shaped distribution; the highly phosphorylated fraction Ph had 14 Pi (± 6). The distribution of sites was highly asymmetric (with 71% of all P-sites in the C-terminal half of Tau). All sites were on Ser or Thr residues, but none were on Tyr. Other known posttranslational modifications were near or below our detection limit (e.g. acetylation, ubiquitination). These findings suggest that normal cellular Tau shows a remarkably high extent of phosphorylation, whereas other modifications are nearly absent. This implies that abnormal phosphorylations at certain sites may not affect the extent of phosphorylation significantly and do not represent hyperphosphorylation. By implication, the pathological aggregation of Tau is not likely a consequence of high phosphorylation.

Programmed ribosomal frameshifting (PRF) is a mechanism used by arteriviruses like porcine reproductive and respiratory syndrome virus (PRRSV) to generate multiple proteins from overlapping reading frames within its RNA genome. PRRSV employs −1 PRF directed by RNA secondary and tertiary structures within its viral genome (canonical PRF), as well as a noncanonical −1 and −2 PRF that are stimulated by the interactions of PRRSV nonstructural protein 1β (nsp1β) and host protein poly(C)-binding protein (PCBP) 1 or 2 with the viral genome. Together, nsp1β and one of the PCBPs act as transactivators that bind a C-rich motif near the shift site to stimulate −1 and −2 PRF, thereby enabling the ribosome to generate two frameshift products that are implicated in viral immune evasion. How nsp1β and PCBP associate with the viral RNA genome remains unclear. Here, we describe the purification of the nsp1β:PCBP2:viral RNA complex on a scale sufficient for structural analysis using small-angle X-ray scattering and stochiometric analysis by analytical ultracentrifugation. The proteins associate with the RNA C-rich motif as a 1:1:1 complex. The monomeric form of nsp1β within the complex differs from previously reported homodimer identified by X-ray crystallography. Functional analysis of the complex via mutational analysis combined with RNA-binding assays and cell-based frameshifting reporter assays reveal a number of key residues within nsp1β and PCBP2 that are involved in complex formation and function. Our results suggest that nsp1β and PCBP2 both interact directly with viral RNA during formation of the complex to coordinate this unusual PRF mechanism.

The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets.

1 July 2020

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What will authorizing the return of US troops mean for Somalia? Explainer Video aboudiaf.drupal 17 June 2022

Ahmed Soliman examines what the reintroduction of US military means for Somalia.

He says the strategy remains to try and reduce al-Shabaab’s threat, suppress its ability to carry out operations, and target its senior leadership.

There is more of a recognition now that the focus needs to be on restoring an effective security sector within Somalia and ensuring their forces are ready, but this also requires better coordination between the federal government and federal member states which it is hoped will happen in this new administration.

What challenges does the new president of Somalia face? Explainer Video aboudiaf.drupal 28 June 2022

Ahmed Soliman examines the challenges the new president Hassan Sheikh Mohamud faces in his first 100 days as president.

Key issues for the new administration are a deteriorating situation with regards to drought as close to half the population are facing food insecurity due to a fourth failed rainy season.

Combined with an inflation rate above ten per cent, many Somalis are at risk of famine and starvation. Many areas of the country are affected from the pastoralist regions to those which house IDP camps around the capital city and other towns, all being exacerbated by the war in Ukraine as Somalia was importing much of its wheat imports from Ukraine and Russia.

Visual Abstract

Visual Abstract

Tricia Rowlison
Dec 1, 2020; 19:2090-2103
Research

Yi Liu
Dec 1, 2020; 19:1968-1985
Research

Matthias Schittmayer
Dec 1, 2020; 19:2104-2114
Research

Jianhua Wang
Nov 4, 2020; 0:RA120.002375v1-mcp.RA120.002375
Research

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles

Oktawia Nilsson
Nov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920
Research Articles

Functions of the gut microbiome have a growing number of implications for host metabolic health, with diet being one of the most significant influences on microbiome composition. Compelling links between diet and the gut microbiome suggest key roles for various macronutrients, including lipids, yet how individual classes of dietary lipids interact with the microbiome remains largely unknown. Sphingolipids are bioactive components of most foods and are also produced by prominent gut microbes. This makes sphingolipids intriguing candidates for shaping diet–microbiome interactions. Here, we used a click chemistry–based approach to track the incorporation of bioorthogonal dietary omega-alkynyl sphinganine (sphinganine alkyne [SAA]) into the murine gut microbial community (Bioorthogonal labeling). We identified microbial and SAA-specific metabolic products through fluorescence-based sorting of SAA-containing microbes (Sort), 16S rRNA gene sequencing to identify the sphingolipid-interacting microbes (Seq), and comparative metabolomics to identify products of SAA assimilation by the microbiome (Spec). Together, this approach, termed Bioorthogonal labeling-Sort-Seq-Spec (BOSSS), revealed that SAA assimilation is nearly exclusively performed by gut Bacteroides, indicating that sphingolipid-producing bacteria play a major role in processing dietary sphinganine. Comparative metabolomics of cecal microbiota from SAA-treated mice revealed conversion of SAA to a suite of dihydroceramides, consistent with metabolic activities of Bacteroides and Bifidobacterium. Additionally, other sphingolipid-interacting microbes were identified with a focus on an uncharacterized ability of Bacteroides and Bifidobacterium to metabolize dietary sphingolipids. We conclude that BOSSS provides a platform to study the flux of virtually any alkyne-labeled metabolite in diet–microbiome interactions.

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.