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Funder: UCB; Id: http://dx.doi.org/10.13039/100011110, Research in chemistry increasingly requires interdisciplinary work prompted by, among other things, advances in computing, machine learning, and artificial intelligence. Everyone working with molecules, whether chemist or not, needs an understanding of the representation of molecules in a machine‐readable format, as this is central to computational chemistry. Four classes of representations are introduced: string, connection table, feature‐based, and computer‐learned representations. Three of the most significant representations are simplified molecular‐input line‐entry system (SMILES), International Chemical Identifier (InChI), and the MDL molfile, of which SMILES was the first to successfully be used in conjunction with a variational autoencoder (VAE) to yield a continuous representation of molecules. This is noteworthy because a continuous representation allows for efficient navigation of the immensely large chemical space of possible molecules. Since 2018, when the first model of this type was published, considerable effort has been put into developing novel and improved methodologies. Most, if not all, researchers in the community make their work easily accessible on GitHub, though discussion of computation time and domain of applicability is often overlooked. Herein, we present questions for consideration in future work which we believe will make chemical VAEs even more accessible. This article is categorized under: Data Science > Chemoinformatics

Viruses are infectious agents that pose significant threats to plants, animals, and humans. The current coronavirus disease 2019 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread globally and resulted in over 2 million deaths and immeasurable financial losses. Rapid and sensitive virus diagnostics become crucially important in controlling the spread of a pandemic before effective treatment and vaccines are available. Gold nanoparticle (AuNP)‐based testing holds great potential for this urgent unmet biomedical need. In this review, we describe the most recent advances in AuNP‐based viral detection applications. In addition, we discuss considerations for the design of AuNP‐based SARS‐CoV‐2 testings. Finally, we highlight and propose important parameters to consider for the future development of effective AuNP‐based testings that would be critical for not only this COVID‐19 pandemic, but also potential future outbreaks. This article is categorized under:Diagnostic Tools > BiosensingDiagnostic Tools > In Vitro Nanoparticle‐Based Sensing, Multifunctional gold nanoparticles enable rapid and effective SARS‐CoV‐2 testing and can be employed for the surveillance and control of COVID‐19 spread.

Climate policies will need to incentivize transformative societal changes if they are to achieve emission reductions consistent with 1.5°C temperature targets. To contribute to efforts for aligning climate policy with broader societal goals, specifically those related to sustainable development, we identify the effects of climate mitigation policy on aspects of socioeconomic development that are known determinants of conflict and evaluate the plausibility and importance of potential pathways to armed conflict and political violence. Conditional on preexisting societal tensions and socioeconomic vulnerabilities, we isolate effects on economic performance, income and livelihood, food and energy prices, and land tenure as most likely to increase conflict risks. Climate policy designs may be critical to moderate these risks as different designs can promote more favorable societal outcomes such as equity and inclusion. Coupling research with careful monitoring and evaluation of the intermediate societal effects at early stages of policy implementation will be a critical part of learning and moderating potential conflict risks. Importantly, better characterizing the future conflict risks under climate policy allows for a more comprehensive comparison to the conflict risk if mitigation is not implemented and graver climate damages are experienced. This article is categorized under:The Carbon Economy and Climate Mitigation > Benefits of Mitigation, Climate policies that emphasize a fair distribution of benefits and compensation for unintended consequences will moderate the risks of violent conflict and future climate impacts.

If each of the four nucleotides were represented equally in the genomes of viruses and the hosts they infect, each base would occur at a frequency of 25%. However, this is not observed in nature. Similarly, the order of nucleotides is not random (e.g., in the human genome, guanine follows cytosine at a frequency of ~0.0125, or a quarter the number of times predicted by random representation). Codon usage and codon order are also nonrandom. Furthermore, nucleotide and codon biases vary between species. Such biases have various drivers, including cellular proteins that recognize specific patterns in nucleic acids, that once triggered, induce mutations or invoke intrinsic or innate immune responses. In this review we examine the types of compositional biases identified in viral genomes and current understanding of the evolutionary mechanisms underpinning these trends. Finally, we consider the potential for large scale synonymous recoding strategies to engineer RNA virus vaccines, including those with pandemic potential, such as influenza A virus and Severe Acute Respiratory Syndrome Coronavirus Virus 2. This article is categorized under:RNA in Disease and Development > RNA in DiseaseRNA Evolution and Genomics > Computational Analyses of RNARNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition, Nucleotide sequences in the genomes of viruses and the hosts they infect are highly patterned; this review discusses the causes, consequences and applications of these genomic compositional biases.

Eukaryotic gene expression is closely regulated by translation and turnover of mRNAs. Recent advances highlight the importance of translation in the control of mRNA degradation, both for aberrant and apparently normal mRNAs. During translation, the information contained in mRNAs is decoded by ribosomes, one codon at a time, and tRNAs, by specifically recognizing codons, translate the nucleotide code into amino acids. Such a decoding step does not process regularly, with various obstacles that can hinder ribosome progression, then leading to ribosome stalling or collisions. The progression of ribosomes is constantly monitored by the cell which has evolved several translation‐dependent mRNA surveillance pathways, including nonsense‐mediated decay (NMD), no‐go decay (NGD), and non‐stop decay (NSD), to degrade certain problematic mRNAs and the incomplete protein products. Recent progress in sequencing and ribosome profiling has made it possible to discover new mechanisms controlling ribosome dynamics, with numerous crosstalks between translation and mRNA decay. We discuss here various translation features critical for mRNA decay, with particular focus on current insights from the complexity of the genetic code and also the emerging role for the ribosome as a regulatory hub orchestrating mRNA decay, quality control, and stress signaling. Even if the interplay between mRNA translation and degradation is no longer to be demonstrated, a better understanding of their precise coordination is worthy of further investigation. This article is categorized under:RNA Turnover and Surveillance > Regulation of RNA StabilityTranslation > Translation RegulationRNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes, The process of mRNA translation is tightly monitored by eukaryotic cells to ensure the correct progression of ribosomes. A multitude of different pathways have evolved to mediate co‐translational mRNA degradation in order to restrict expression of aberrant mRNAs but also that of functional mRNAs.

It has been almost two decades since the first link between microRNAs and cancer was established. In the ensuing years, this abundant class of short noncoding regulatory RNAs has been studied in virtually all cancer types. This tremendously large body of research has generated innovative technological advances for detection of microRNAs in tissue and bodily fluids, identified the diagnostic, prognostic, and/or predictive value of individual microRNAs or microRNA signatures as potential biomarkers for patient management, shed light on regulatory mechanisms of RNA–RNA interactions that modulate gene expression, uncovered cell‐autonomous and cell‐to‐cell communication roles of specific microRNAs, and developed a battery of viral and nonviral delivery approaches for therapeutic intervention. Despite these intense and prolific research efforts in preclinical and clinical settings, there are a limited number of microRNA‐based applications that have been incorporated into clinical practice. We review recent literature and ongoing clinical trials that highlight most promising approaches and standing challenges to translate these findings into viable microRNA‐based clinical tools for cancer medicine. This article is categorized under:RNA in Disease and Development > RNA in Disease, microRNAs are short noncoding regulatory RNAs with important roles in cancer biology. microRNAs are informative biomarkers for early cancer detection and treatment decisions. microRNAs are being evaluated in clinical trials as new drugs for personalized cancer medicine.

An RNA structure prediction from a single‐sequence RNA folding program is not evidence for an RNA whose structure is important for function. Random sequences have plausible and complex predicted structures not easily distinguishable from those of structural RNAs. How to tell when an RNA has a conserved structure is a question that requires looking at the evolutionary signature left by the conserved RNA. This question is important not just for long noncoding RNAs which usually lack an identified function, but also for RNA binding protein motifs which can be single stranded RNAs or structures. Here we review recent advances using sequence and structural analysis to determine when RNA structure is conserved or not. Although covariation measures assess structural RNA conservation, one must distinguish covariation due to RNA structure from covariation due to independent phylogenetic substitutions. We review a statistical test to measure false positives expected under the null hypothesis of phylogenetic covariation alone (specificity). We also review a complementary test that measures power, that is, expected covariation derived from sequence variation alone (sensitivity). Power in the absence of covariation signals the absence of a conserved RNA structure. We analyze artifacts that falsely identify conserved RNA structure such as the misuse of programs that do not assess significance, the use of inappropriate statistics confounded by signals other than covariation, or misalignments that induce spurious covariation. Among artifacts that obscure the signal of a conserved RNA structure, we discuss the inclusion of pseudogenes in alignments which increase power but destroy covariation. This article is categorized under:RNA Structure and Dynamics > RNA Structure, Dynamics and ChemistryRNA Evolution and Genomics > Computational Analyses of RNARNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution, Covariation together with covariation power allow to distinguish between three different conservation patterns in RNA alignments. Structural RNAs with evolutionary signal for a conserved structure have covariation and power (green). Non structural RNAs have power but no covariation (red). RNAs that lack both covariation and power are too conserved in sequence to be able to decide whether they have a conserved structure or not (blue). We show the covariation versus power observed in structural RNAs from the database Rfam (black), and the covariation and power for the long non‐coding RNAs HOTAIR, RepA‐Xist, and ncSRA that do not support a conserved RNA structure (brown)

Several human coronaviruses (HCoVs) are distinguished by the ability to generate epidemics or pandemics, with their corresponding diseases characterized by severe respiratory illness, such as that which occurs in severe acute respiratory syndrome (SARS‐CoV), Middle East respiratory syndrome (MERS‐CoV), and, today, in SARS‐CoV‐2, an outbreak that has struck explosively and uncontrollably beginning in December 2019 and has claimed the lives of more than 1.9 M people worldwide as of January 2021. The development of vaccines has taken one year, which is why it is necessary to investigate whether some already‐existing alternatives that have been successfully developed in recent years can mitigate the pandemic's advance. Silver nanoparticles (AgNPs) have proved effective in antiviral action. Thus, in this review, several in vitro and in vivo studies of the effect of AgNPs on viruses that cause respiratory diseases are analyzed and discussed to promote an understanding of the possible interaction of AgNPs with SARS‐CoV‐2. The study focuses on several in vivo toxicological studies of AgNPs and a dose extrapolation to humans to determine the chief avenue of exposure. It can be concluded that the use of AgNPs as a possible treatment for SARS‐CoV‐2 could be viable, based on comparing the virus' behavior to that of similar viruses in in vivo studies, and that the suggested route of administration in terms of least degree of adverse effects is inhalation. This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory DiseaseToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials, Bats are natural carriers of the new SARS‐CoV‐2 coronavirus, which can be transmitted to humans through certain intermediate hosts. AgNPs allow the internalization of the virus in the cells to be avoided by inhibiting the interaction between the spike (S) glycoprotein and its specific receptor. This study summarizes in vitro and in vivo studies in which AgNPs were used to counteract different viruses that cause respiratory diseases. In addition, the possible routes of AgNPs exposure and dose extrapolation to humans as a possible treatment for SARS‐CoV‐2 are analyzed.

Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather than being homogeneous machines responsible for mRNA translation, ribosomes are highly heterogeneous and can play an active part in translational regulation. These “specialized ribosomes” comprise of specific protein and/or rRNA components, which are required for the translation of particular mRNAs. However, while there is extensive evidence for ribosome heterogeneity, support for specialized functions is limited. Recent work in a variety of developmental model organisms has shed some light on the biological relevance of ribosome heterogeneity. Tissue‐specific expression of ribosomal components along with phenotypic analysis of ribosomal gene mutations indicate that ribosome heterogeneity and potentially specialization are common in key development processes like embryogenesis, spermatogenesis, oogenesis, body patterning, and neurogenesis. Several examples of ribosome specialization have now been proposed but strong links between ribosome heterogeneity, translation of specific mRNAs by defined mechanisms, and role of these translation events remain elusive. Furthermore, several studies have indicated that heterogeneous ribosome populations are a product of tissue‐specific expression rather than specialized function and that ribosomal protein phenotypes are the result of extra‐ribosomal function or overall reduced ribosome levels. Many important questions still need to be addressed in order to determine the functional importance of ribosome heterogeneity to development and disease, which is likely to vary across systems. It will be essential to dissect these issues to fully understand diseases caused by disruptions to ribosomal composition, such as ribosomopathies. This article is categorized under:Translation > Translation RegulationTranslation > Ribosome Structure/FunctionRNA in Disease and Development > RNA in Development, Ribosome heterogeneity is found across a variety of species and its potential importance to development is being assessed to determine if these ribosomes are specialized.

Viruses are among the most infectious pathogens, responsible for the highest death toll around the world. Lack of effective clinical drug for most of the viruses emphasizes the rapid and accurate diagnosis at early stages of infection to prevent rapid spread of the pathogens. Nanotechnology is an emerging field with applications in various domains, where nano‐biomedical science has many significant contributions such as effective delivery of drugs/therapeutic molecules to specific organs, imaging, sensitive detection of virus, and their accurate tracking in host cells. The nanomaterials reported for virus detection and tracking mainly include magnetic and gold NPs, ZnO/Pt‐Pd, graphene, and quantum dots (QDs). In addition, the single virus tracking technology (SVT) allowed to track the life cycle stages of an individual virus for better understanding of their dynamics within the living cells. Inorganic as well as non‐metallic fluorescent materials share the advantages of high photochemical stability, a wide range of light absorption curves and polychromatic emission. Hence, are considered as potential fluorescent nano‐probes for SVT. However, there are still some challenges: (i) clinical false positive rate of some detection methods is still high; (ii) in the virus tracking process, less adaptability of QDs owing to larger size, flicker, and possible interference with virus function; and (iii) in vivo tracking of a single virus, in real time needs further refinement. In the future, smaller, non‐toxic, and chemically stable nanomaterials are needed to improve the efficiency and accuracy of detection, and monitoring of virus infections to curb the mortalities. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious DiseaseBiology‐Inspired Nanomaterials > Protein and Virus‐Based Structures, Nano‐particles and their applications in virus detection and tracking to comprehend infection mechanisms.

Given their intrinsic pleiotropism, microRNAs (miR) play complex biological roles, in both normal and pathological conditions. Often the same miR can act as oncogene or oncosuppressor, depending on the biological process dysregulated in each specific tissue. miR‐223 does not represent an exception to this rule and its functions greatly differ in different contexts. miR‐223 has been widely studied in the hematopoietic compartment, where it plays a central role in innate immune response, regulating myeloid differentiation and granulocytes function. Accordingly, dysregulated expression of miR‐223 has been associated to different inflammatory disorders and tumors arising from the immune compartment. Most carcinomas, breast cancer being the most studied, display loss of miR‐223. However, in gastro‐esophageal cancers miR‐223 is frequently overexpressed and correlates with worse prognosis. A link between miR‐223 and response to CDK4/6‐inhibitors has been recently proposed, suggesting a role as biomarker of therapeutic response. The notion that one of the most commonly mutated protein in cancer, mutant p53, binds the promoter of miR‐223 and suppresses its transcription, adds a further level of complexity to the full understanding of miR‐223 in cancer. In this review, we will summarize the current knowledge on the molecular networks that alter or are altered by miR‐223, in different cancer types. We will discuss if the times are ready for the exploitation of miR‐223 as predictive biomarker of treatment response or, even, as therapeutic target, in specific settings. Finally, we will suggest which could be the next steps to be taken for a realistic clinical application of miR‐223. This article is categorized under:RNA in Disease and Development > RNA in Disease, miR‐223–centered view of the Hallmarks of Cancer. Many of the hallmarks of cancer can be affected by miR‐223 up‐regulation or down‐regulation, via different modulation of its targets and depending on the tumor type. These aspects of miR‐223 biology support the possibility that it could serve as prognostic/predictive biomarker and therapeutic target, in certain tumoral contexts.

Cancer nanomedicine has evolved in recent years and is only expected to increase due to the ease with which nanomaterials (NMs) may be manipulated to the advantage of the cancer patient. The success of nanomedicine is dependent on the cell death mechanism, which in turn is dependent on the organelle initially targeted. The success of cancer nanomedicine is also dependent on other cellular mechanisms such as the induction of autophagy dysfunction, manipulation of the tumor microenvironment (TME) and secretome or induction of host immune responses. Current cancer phototherapies for example, photothermal‐ or photodynamic therapies as well as radio enhancement also form a major part of cancer nanomedicine. In general, cancer nanomedicine may be grouped into those NMs exhibiting inherent anti‐cancer properties that is, self‐therapeutic NMs (Group 1), NMs leading to localization of phototherapies or radio‐enhancement (Group 2), and NMs as nanocarriers in the absence or presence of external radiation (Group 3). The recent advances of these three groups, together with their advantages and disadvantages as well as their cellular mechanisms and ultimate outcomes are summarized in this review. By exploiting these different intracellular mechanisms involved in initiating cell death pathways, it is possible to synthesize NMs that may have the desirable characteristics to maximize their efficacy in cancer therapy. Therefore, a summary of these important physicochemical characteristics is also presented that need to be considered for optimal cancer cell targeting and initiation of mechanisms that will lead to cancerous cell death. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseToxicology and Regulatory Issues in Nanomedicine > Toxicology of NanomaterialsToxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine, Cellular mechanisms exploited in cancer nanomedicine.

microRNAs (miRNAs) play a central role in the regulation of gene expression by targeting specific mRNAs for degradation or translational repression. Each miRNA is post‐transcriptionally processed into a duplex comprising two strands. One of the two miRNA strands is selectively loaded into an Argonaute protein to form the miRNA‐Induced Silencing Complex (miRISC) in a process referred to as miRNA strand selection. The other strand is ejected from the complex and is subject to degradation. The target gene specificity of miRISC is determined by sequence complementarity between the Argonaute‐loaded miRNA strand and target mRNA. Each strand of the miRNA duplex has the capacity to be loaded into miRISC and possesses a unique seed sequence. Therefore, miRNA strand selection plays a defining role in dictating the specificity of miRISC toward its targets and provides a mechanism to alter gene expression in a switch‐like fashion. Aberrant strand selection can lead to altered gene regulation by miRISC and is observed in several human diseases including cancer. Previous and emerging data shape the rules governing miRNA strand selection and shed light on how these rules can be circumvented in various physiological and pathological contexts. This article is categorized under:RNA Processing > Processing of Small RNAsRegulatory RNAs/RNAi/Riboswitches > Regulatory RNAsRegulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs, Summary of miRNA strand selection and regulatory mechanisms. Three major points of regulation for miRNA strand selection (1) altered miRNA processing by the Microprocessor complex (not shown) or Dicer, (2) remodeling of the miRNA duplex by nontemplated RNA modifications such as uridylation or A‐to‐I editing, and (3) changes in the strand preference of Argonaute. Once presented with a miRNA duplex, Argonaute makes a binary choice to load one miRNA strand and discard the other strand from miRISC. Alternate Argonaute programming leads to shifts in the target profile of miRISC based on the seed sequence of the loaded strand and is sometimes associated with human diseases.

Ribosomal protein genes are among the most highly expressed genes in most cell types. Their products are generally essential for ribosome synthesis, which is the cornerstone for cell growth and proliferation. Many cellular resources are dedicated to producing ribosomal proteins and thus this process needs to be regulated in ways that carefully balance the supply of nascent ribosomal proteins with the demand for new ribosomes. Ribosomal protein genes have classically been viewed as a uniform interconnected regulon regulated in eukaryotic cells by target of rapamycin and protein kinase A pathway in response to changes in growth conditions and/or cellular status. However, recent literature depicts a more complex picture in which the amount of ribosomal proteins produced varies between genes in response to two overlapping regulatory circuits. The first includes the classical general ribosome‐producing program and the second is a gene‐specific feature responsible for fine‐tuning the amount of ribosomal proteins produced from each individual ribosomal gene. Unlike the general pathway that is mainly controlled at the level of transcription and translation, this specific regulation of ribosomal protein genes is largely achieved through changes in pre‐mRNA splicing efficiency and mRNA stability. By combining general and specific regulation, the cell can coordinate ribosome production, while allowing functional specialization and diversity. Here we review the many ways ribosomal protein genes are regulated, with special focus on the emerging role of posttranscriptional regulatory events in fine‐tuning the expression of ribosomal protein genes and its role in controlling the potential variation in ribosome functions. This article is categorized under:Translation > Ribosome BiogenesisTranslation > Ribosome Structure/FunctionTranslation > Translation Regulation, Global circuit of ribosome synthesis.

Translation control is crucial during virus–host interaction. On one hand, viruses completely rely on the protein synthesis machinery of host cells to propagate and have evolved various mechanisms to redirect the host's ribosomes toward their viral mRNAs. On the other hand, the host rewires its translation program in an attempt to contain and suppress the virus early on during infection; the antiviral program includes specific control on protein synthesis to translate several antiviral mRNAs involved in quenching the infection. As the infection progresses, host translation is in turn inhibited in order to limit viral propagation. We have learnt of very diverse strategies that both parties utilize to gain or retain control over the protein synthesis machinery. Yet novel strategies continue to be discovered, attesting for the importance of mRNA translation in virus–host interaction. This review focuses on recently described translation strategies employed by both hosts and viruses. These discoveries provide additional pieces in the understanding of the complex virus–host translation landscape. This article is categorized under:Translation > Translation MechanismsTranslation > Translation Regulation, Translation control of mammalian cells during viral infection can be impacted by tRNA fragments, N6‐methyladenosine (m6A), or modified tRNA pools.

Coronaviruses, including SARS‐Cov‐2, are RNA‐based pathogens that interface with a large variety of RNA‐related cellular processes during infection. These processes include capping, polyadenylation, localization, RNA stability, translation, and regulation by RNA binding proteins or noncoding RNA effectors. The goal of this article is to provide an in‐depth perspective on the current state of knowledge of how various coronaviruses interact with, usurp, and/or avoid aspects of these cellular RNA biology machineries. A thorough understanding of how coronaviruses interact with RNA‐related posttranscriptional processes in the cell should allow for new insights into aspects of viral pathogenesis as well as identify new potential avenues for the development of anti‐coronaviral therapeutics. This article is categorized under:RNA in Disease and Development > RNA in Disease, Coronavirus interplay with mechanisms associated with the RNA biology of the host cell play a key role in numerous aspects of virus replication and pathogenesis.

The T‐box riboswitches are widespread bacterial noncoding RNAs that directly bind specific tRNAs, sense aminoacylation on bound tRNAs, and switch conformations to control amino‐acid metabolism and to maintain nutritional homeostasis. The core mechanisms of tRNA recognition, amino acid sensing, and conformational switching by the T‐boxes have been recently elucidated, providing a wealth of new insights into multivalent and multimodal RNA–RNA interactions. This review dissects the structures and tRNA‐recognition mechanisms by the Stem I, Stem II, and Discriminator domains, which collectively compose the T‐box riboswitches. It further compares and contrasts the two classes of T‐boxes that regulate transcription and translation, respectively, and integrates recent findings to derive general themes, trends, and insights into complex RNA–RNA interactions. Specifically, the T‐box paradigm reveals that noncoding RNAs can interact with each other through multiple coordinated contacts, concatenation of stacked helices, and mutually induced fit. Numerous tertiary contacts, especially those emanating from strings of single‐stranded purines, act in concert to reinforce long‐range base‐pairing and stacking interactions. These coordinated, mixed‐mode contacts allow the T‐box RNA to sterically sense aminoacylation on the tRNA using a bipartite steric sieve, and to couple this readout to a conformational switch mediated by tRNA‐T‐box stacking. Together, the insights gleaned from the T‐box riboswitches inform investigations into other complex RNA structures and assemblies, development of T‐box‐targeted antimicrobials, and may inspire design and engineering of novel RNA sensors, regulators, and interfaces. This article is categorized under:RNA Structure and Dynamics > RNA Structure, Dynamics and ChemistryRegulatory RNAs/RNAi/Riboswitches > Regulatory RNAsRegulatory RNAs/RNAi/Riboswitches > Riboswitches, Recent elucidation of the structures and mechanisms of bacterial T‐box riboswitches provides insights into how structured noncoding RNAs interact with each other and regulate gene expression through multivalent contacts that go much beyond base pairing.

Viruses are highly ordered supramolecular complexes that have evolved to propagate by hijacking the host cell's machinery. Although viruses are very diverse, spreading through cells of all kingdoms of life, they share common functions and properties. Next to the general interest in virology, fundamental viral mechanisms are of growing importance in other disciplines such as biomedicine and (bio)nanotechnology. However, in order to optimally make use of viruses and virus‐like particles, for instance as vehicle for targeted drug delivery or as building blocks in electronics, it is essential to understand their basic chemical and physical properties and characteristics. In this context, the number of studies addressing the mechanisms governing viral properties and processes has recently grown drastically. This review summarizes a specific part of these scientific achievements, particularly addressing physical virology approaches aimed to understand the self‐assembly of viruses and the mechanical properties of viral particles. Using a physicochemical perspective, we have focused on fundamental studies providing an overview of the molecular basis governing these key aspects of viral systems. This article is categorized under:Biology‐Inspired Nanomaterials > Protein and Virus‐Based StructuresNanotechnology Approaches to Biology > Nanoscale Systems in Biology, Viruses are highly ordered supramolecular complexes that have evolved to propagate between related organisms. Although viruses are very diverse, they share common functions and properties. In this review, we aim to provide an overview of virus self‐assembly and viral particle mechanics, summarizing the latest scientific achievements within these areas.

It has been nearly 63 years since the first characterization of an RNA triple helix in vitro by Gary Felsenfeld, David Davies, and Alexander Rich. An RNA triple helix consists of three strands: A Watson–Crick RNA double helix whose major‐groove establishes hydrogen bonds with the so‐called “third strand”. In the past 15 years, it has been recognized that these major‐groove RNA triple helices, like single‐stranded and double‐stranded RNA, also mediate prominent biological roles inside cells. Thus far, these triple helices are known to mediate catalysis during telomere synthesis and RNA splicing, bind to ligands and ions so that metabolite‐sensing riboswitches can regulate gene expression, and provide a clever strategy to protect the 3′ end of RNA from degradation. Because RNA triple helices play important roles in biology, there is a renewed interest in better understanding the fundamental properties of RNA triple helices and developing methods for their high‐throughput discovery. This review provides an overview of the fundamental biochemical and structural properties of major‐groove RNA triple helices, summarizes the structure and function of naturally occurring RNA triple helices, and describes prospective strategies to isolate RNA triple helices as a means to establish the “triplexome”. This article is categorized under:RNA Structure and Dynamics > RNA Structure and DynamicsRNA Structure and Dynamics > RNA Structure, Dynamics and ChemistryRNA Structure and Dynamics > Influence of RNA Structure in Biological Systems, The three‐dimensional structures of naturally occurring RNA triple helices are displayed with the three strands denoted in blue, purple, and green. Collectively, these RNA triple helices play important biological roles in catalysis, binding to ligands (orange), and stabilizing RNA.

While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug‐loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size‐dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non‐invasive in vivo imaging modalities. This allows for visualization and quantification of the whole‐body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non‐invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state‐of‐the‐art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseDiagnostic Tools > in vivo Nanodiagnostics and ImagingNanotechnology Approaches to Biology > Nanoscale Systems in Biology, Pharmacological evaluation of nanoparticles and antibodies performed through quantitative imaging‐guided mathematical models.

Poly(ADP‐ribose) polymerases (PARPs) are abundant nuclear proteins that synthesize ADP ribose polymers (pADPr) and catalyze the addition of (p)ADPr to target biomolecules. PARP1, the most abundant and well‐studied PARP, is a multifunctional enzyme that participates in numerous critical cellular processes. A considerable amount of PARP research has focused on PARP1's role in DNA damage. However, an increasing body of evidence outlines more routine roles for PARP and PARylation in nearly every step of RNA biogenesis and metabolism. PARP1's involvement in these RNA processes is pleiotropic and has been ascribed to PARP1's unique flexible domain structures. PARP1 domains are modular self‐arranged enabling it to recognize structurally diverse substrates and to act simultaneously through multiple discrete mechanisms. These mechanisms include direct PARP1‐protein binding, PARP1‐nucleic acid binding, covalent PARylation of target molecules, covalent autoPARylation, and induction of noncovalent interactions with PAR molecules. A combination of these mechanisms has been implicated in PARP1's context‐specific regulation of RNA biogenesis and metabolism. We examine the mechanisms of PARP1 regulation in transcription initiation, elongation and termination, co‐transcriptional splicing, RNA export, and post‐transcriptional RNA processing. Finally, we consider promising new investigative avenues for PARP1 involvement in these processes with an emphasis on PARP1 regulation of subcellular condensates. This article is categorized under:RNA Processing > Splicing Regulation/Alternative Splicing, PARP1 plays functional roles in the mRNA life cycle: from biogenesis (transcription, splicing, and polyadenylation) to modifications (m6A), stability, export, and ribosome assembly (translation). This regulation occurs either through its direct binding to its binding partners (DNA, RNA, protein) and/or through PARylation or PAR recognition by target molecules.

Pro‐inflammatory signals induce metabolic reprogramming in innate and adaptive immune cells of both myeloid and lymphoid lineage, characterized by a shift to aerobic glycolysis akin to the Warburg effect first described in cancer. Blocking the switch to aerobic glycolysis impairs the survival, differentiation, and effector functions of pro‐inflammatory cell types while favoring anti‐inflammatory and regulatory phenotypes. Glycolytic reprogramming may therefore represent a selective vulnerability of inflammatory immune cells, providing an opportunity to modulate immune responses in autoimmune disease without broad toxicity in other tissues of the body. The mechanisms by which aerobic glycolysis and the balance between glycolysis and oxidative phosphorylation regulate immune responses have only begun to be understood, with many additional insights expected in the years to come. Immunometabolic therapies targeting aerobic glycolysis include both pharmacologic inhibitors of key enzymes and glucose‐restricted diets, such as the ketogenic diet. Animal studies support a role for these pharmacologic and dietary therapies for the treatment of autoimmune diseases, and in a few cases proof of concept has been demonstrated in human disease. Nonetheless, much more work is needed to establish the clinical safety and efficacy of these treatments. This article is categorized under:Biological Mechanisms > MetabolismTranslational, Genomic, and Systems Medicine > Translational MedicineBiological Mechanisms > Cell Signaling, The immunologic Warburg effect represents a potential target for treating autoimmune diseases, through both pharmacologic and dietary strategies. The mechanisms explaining the requirement for aerobic glycolysis in immune activation remain only partially understood.

Cardiac electrophysiology models are among the most mature and well‐studied mathematical models of biological systems. This maturity is bringing new challenges as models are being used increasingly to make quantitative rather than qualitative predictions. As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model. This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology. We discuss the classic and latest approaches to calibration in the electrophysiology field, at both the ion channel and cellular AP scales. We end with a discussion of the many challenges that work to date has raised and the need for reproducible descriptions of the calibration process to enable models to be recalibrated to new data sets and built upon for new studies. This article is categorized under:Analytical and Computational Methods > Computational MethodsPhysiology > Mammalian Physiology in Health and DiseaseModels of Systems Properties and Processes > Cellular Models, A schematic of a cardiac electrophysiology model, highlighting the components described by equations that need to be calibrated using experimental data.

Embryonic anterior–posterior patterning is established in Drosophila melanogaster by maternally expressed genes. The mRNAs of several of these genes accumulate at either the anterior or posterior pole of the oocyte via a number of mechanisms. Many of these mRNAs are also under elaborate translational regulation. Asymmetric RNA localization coupled with spatially restricted translation ensures that their proteins are restricted to the position necessary for the developmental process that they drive. Bicoid (Bcd), the anterior determinant, and Oskar (Osk), the determinant for primordial germ cells and posterior patterning, have been studied particularly closely. In early embryos an anterior–posterior gradient of Bcd is established, activating transcription of different sets of zygotic genes depending on local Bcd concentration. At the posterior pole, Osk seeds formation of polar granules, ribonucleoprotein complexes that accumulate further mRNAs and proteins involved in posterior patterning and germ cell specification. After fertilization, polar granules associate with posterior nuclei and mature into nuclear germ granules. Osk accumulates in these granules, and either by itself or as part of the granules, stimulates germ cell division. This article is categorized under:RNA Export and Localization > RNA LocalizationTranslation > Translation RegulationRNA in Disease and Development > RNA in Development, Where the fly embryo forms its head and its abdomen is determined by maternal RNAs that are transported to the anterior or posterior poles of the developing oocyte, where they are anchored and translationally activated through complex and fascinating mechanisms.

Active immunotherapy of cancer aims to treat the disease by inducing effective cellular and humoral immune responses. Virus‐like particle‐based vaccines have evolved dramatically over the last few decades, greatly reducing morbidity and mortality of several infectious diseases and expectedly preventing cervical cancer caused by human papilloma virus. In contrast to these broad successes of disease prevention, therapeutic cancer vaccines remain to demonstrate clinical benefit. Yet, several preclinical and clinical trials have revealed promising results and are paving the way for medical breakthroughs. This study reviews and discusses the recent preclinical development and clinical trials in this field. This article is categorized under: Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology, Virus‐like particles, a powerful and flexible platform for the development of cancer vaccines.

It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate‐induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti‐tumor immune response. This article is characterized under:Biological Mechanisms > Metabolism, Immune cells ‘sense’ high concentration of lactate which accumulates at the site of inflammation or tumor as result of accelerated metabolism of immune, stromal, or cancer cells.

As a consequence of recent progression in biomedicine and nanotechnology, nanomedicine has emerged rapidly as a new discipline with extensive application of nanomaterials in biology, medicine, and pharmacology. Among the various nanomaterials, silica nanoparticles (SNPs) are particularly promising in nanomedicine applications due to their large specific surface area, adjustable pore size, facile surface modification, and excellent biocompatibility. This paper reviews the synthesis of SNPs and their recent usage in drug delivery, biomedical imaging, photodynamic and photothermal therapy, and other applications. In addition, the possible adverse effects of SNPs in nanomedicine applications are reviewed from reported in vitro and in vivo studies. Finally, the potential opportunities and challenges for the future use of SNPs are discussed. This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Emerging Technologies, Schematic diagram of silica nanoparticles applied to different nanomedicine.

Under the broader category of extracellular vesicles (EVs), exosomes are now well recognized for their contribution and potential for biomedical research. During the last ten years, numerous technologies for purification and characterization of EVs have been developed. This enhanced knowledge has resulted in the development of novel applications of EVs. This review is an attempt to capture the exponential growth observed in EV science in the last decade and discuss the future potential to improve our understanding of EVs, develop technologies to overcome current limitations, and advance their utility for human benefit, especially in cancer medicine. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging TechnologiesTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease, Landscape of extracellular vesicles in biology and disease.

Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 “Immunotoxicity Studies for Human Pharmaceuticals” of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH‐S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH‐S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials, Proposed strategy for immunotoxicity assessment of nanomedicinal products.

Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The “omics” revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross‐talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems‐level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis. This article is categorized under:Physiology > Mammalian Physiology in Health and DiseaseDevelopmental Biology > Developmental Processes in Health and DiseaseModels of Systems Properties and Processes > Cellular Models, The current review focuses on molecular structure and function of the various components of muscle physiology. Within each component, we highlight the necessary molecular mechanisms and cross‐talk critical for defining the state of muscle health. We also highlight instances of aberrant molecular mechanisms underlying disease.

In the current literature, there are few experimental tests of capacities for cumulative cultural evolution in nonhuman species. There are even fewer examples of such tests in young children. This limited evidence is noteworthy given widespread interest in the apparent distinctiveness of human cumulative culture, and the potentially significant theoretical implications of identifying related capacities in nonhumans or very young children. We evaluate experimental methods upon which claims of capacities for cumulative culture, or lack thereof, have been based. Although some of the established methods (those simulating generational succession) have the potential to identify positive evidence that fulfills widely accepted definitions of cumulative culture, the implementation of these methods entails significant logistical challenges. This is particularly true for testing populations that are difficult to access in large numbers, or those not amenable to experimental control. This presents problems for generating evidence that would be sufficient to support claims of capacities for cumulative culture, and these problems are magnified for establishing convincing negative evidence. We discuss alternative approaches to assessing capacities for cumulative culture, which circumvent logistical problems associated with experimental designs involving chains of learners. By inferring the outcome of repeated transmission from the input–output response patterns of individual subjects, sample size requirements can be massively reduced. Such methods could facilitate comparisons between populations, for example, different species, or children of a range of ages. We also detail limitations and challenges of this alternative approach, and discuss potential avenues for future research. This article is categorized under:Cognitive Biology > Evolutionary Roots of CognitionCognitive Biology > Cognitive DevelopmentPsychology > Comparative Psychology, Methods of assessing capacities for cumulative culture. Top: solution success increases in a chain of multiple individuals attempting a single problem. Below: solution success increases with demonstration success in single individuals attempting multiple problems.

Colorectal cancer remains a significant cause of morbidity and mortality worldwide. Half of all patients develop liver metastases, presenting unique challenges for their treatment. The shortcomings of conventional chemotherapy has encouraged the use of nanomedicines; the application of nanotechnology in the diagnosis and treatment of disease. In spite of technological improvements in nanotechnology, the complexity of biological systems hinders the prospect of nanomedicines being applied in cancer therapy at the present time. This review highlights current biological barriers and discusses aspects of tumor biology together with the physicochemical features of the nanocarrier, that need to be considered in order to develop effective nanotherapeutics for colorectal cancer patients with liver metastases. It becomes clear that incorporating an interdisciplinary approach when developing nanomedicines should assure appropriate disease‐driven design and that this will form a critical step in improving their clinical translation. This article is characterized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease, A fundamental understanding of the tumor biology and its physiological features is necessary for the design and development of effective nanomedicines to target cancers.

Successful development depends on the precise tissue‐specific regulation of genes by enhancers, genetic elements that act as switches to control when and where genes are expressed. Because enhancers are critical for development, and the majority of disease‐associated mutations reside within enhancers, it is essential to understand which sequences within enhancers are important for function. Advances in sequencing technology have enabled the rapid generation of genomic data that predict putative active enhancers, but functionally validating these sequences at scale remains a fundamental challenge. Herein, we discuss the power of genome‐wide strategies used to identify candidate enhancers, and also highlight limitations and misconceptions that have arisen from these data. We discuss the use of massively parallel reporter assays to test enhancers for function at scale. We also review recent advances in our ability to study gene regulation during development, including CRISPR‐based tools to manipulate genomes and single‐cell transcriptomics to finely map gene expression. Finally, we look ahead to a synthesis of complementary genomic approaches that will advance our understanding of enhancer function during development. This article is categorized under:Physiology > Mammalian Physiology in Health and DiseaseDevelopmental Biology > Developmental Processes in Health and DiseaseLaboratory Methods and Technologies > Genetic/Genomic Methods, The correct spatiotemporal regulation of genes by enhancers is critical for successful development from a single fertilized egg to a complex multicellular organism. Herein, we discuss current genome‐wide approaches to identify enhancers and to dissect enhancer function. Figure created with BioRender.

Sahel rainfall is dynamically linked to the global Hadley cell and to the regional monsoon circulation. It is therefore susceptible to forcings from remote oceans and regional land alike. Warming of the oceans enhances the stability of the tropical atmosphere and weakens deep ascent in the Hadley circulation. Warming of the Sahara and of the nearby oceans changes the structure and position of the regional shallow circulation and allows more of the intense convective systems that determine seasonal rain accumulation. These processes can explain the observed interannual to multidecadal variability. Sea surface temperature anomalies were the dominant forcing of the drought of the 1970s and 1980s. In most recent decades, seasonal rainfall amounts have partially recovered, but rainy season characteristics have changed: rainfall is more intense and intermittent and wetting is concentrated in the late rainy season and away from the west coast. Similar subseasonal and subregional differences in rainfall trends characterize the simulated response to increased greenhouse gases, suggesting an anthropogenic influence. While uncertainty in future projections remains, confidence in them is encouraged by the recognition that seasonal mean rainfall depends on large‐scale drivers of atmospheric circulations that are well resolved by current climate models. Nevertheless, observational and modeling efforts are needed to provide more refined projections of rainfall changes, expanding beyond total accumulation to metrics of intraseasonal characteristics and risk of extreme events, and coordination between climate scientists and stakeholders is needed to generate relevant information that is useful even under deep uncertainty. This article is categorized under:Paleoclimates and Current Trends > Modern Climate Change

Recent advances in genetic manipulation and genome sequencing have paved the way for a new generation of research organisms. The amphipod crustacean Parhyale hawaiensis is one such system. Parhyale are easy to rear and offer large broods of embryos amenable to injection, dissection, and live imaging. Foundational work has described Parhyale embryonic development, while advancements in genetic manipulation using CRISPR‐Cas9 and other techniques, combined with genome and transcriptome sequencing, have enabled its use in studies of arthropod development, evolution, and regeneration. This study introduces Parhyale development and life history, a catalog of techniques and resources for Parhyale research, and two case studies illustrating its power as a comparative research system. This article is categorized under:Comparative Development and Evolution > Evolutionary NoveltiesAdult Stem Cells, Tissue Renewal, and Regeneration > RegenerationComparative Development and Evolution > Model SystemsComparative Development and Evolution > Body Plan Evolution

Self‐control is critical for both humans and nonhuman animals because it underlies complex cognitive abilities, such as decision‐making and future planning, enabling goal‐directed behavior. For instance, it is positively associated with social competence and life success measures in humans. We present the first review of delay of gratification as a measure of self‐control in nonhuman primates, corvids (crow family) and psittacines (parrot order): disparate groups that show comparable advanced cognitive abilities and similar socio‐ecological factors. We compare delay of gratification performance and identify key issues and outstanding areas for future research, including finding the best measures and drivers of delayed gratification. Our review therefore contributes to our understanding of both delayed gratification as a measure of self‐control and of complex cognition in animals. This article is categorized under:Cognitive Biology > Evolutionary Roots of CognitionPsychology > Comparative Psychology, Examples of delayed gratification tasks. (a) Exchange task with a corvid: subject can choose to swap a token (e.g., bottle top) for a reward after a delay; (b) Intertemporal choice: monkey can select the immediately available reward or wait for the delayed reward from a rotating tray.

Numerous post‐transcriptional RNA processes play a major role in regulating the quantity, quality and diversity of gene expression in the cell. These include RNA processing events such as capping, splicing, polyadenylation and modification, but also aspects such as RNA localization, decay, translation, and non‐coding RNA‐associated regulation. The interface between the transcripts of RNA viruses and the various RNA regulatory processes in the cell, therefore, has high potential to significantly impact virus gene expression, regulation, cytopathology and pathogenesis. Furthermore, understanding RNA biology from the perspective of an RNA virus can shed considerable light on the broad impact of these post‐transcriptional processes in cell biology. Thus the goal of this article is to provide an overview of the richness of cellular RNA biology and how RNA viruses use, usurp and/or avoid the associated machinery to impact the outcome of infection. This article is categorized under:RNA in Disease and Development > RNA in Disease, RNA Viruses influence a multitude of cellular pathways leading to disregulated gene expression.

Upon viral infection, a tug of war is triggered between host cells and viruses to maintain/gain control of vital cellular functions, the result of which will ultimately dictate the fate of the host cell. Among these essential cellular functions, alternative splicing (AS) is an important RNA maturation step that allows exons, or parts of exons, and introns to be retained in mature transcripts, thereby expanding proteome diversity and function. AS is widespread in higher eukaryotes, as it is estimated that nearly all genes in humans are alternatively spliced. Recent evidence has shown that upon infection by numerous viruses, the AS landscape of host‐cells is affected. In this review, we summarize recent advances in our understanding of how virus infection impacts the AS of cellular transcripts. We also present various molecular mechanisms allowing viruses to modulate cellular AS. Finally, the functional consequences of these changes in the RNA splicing signatures during virus–host interactions are discussed. This article is categorized under:RNA in Disease and Development > RNA in DiseaseRNA Processing > Splicing Regulation/Alternative Splicing

Processing and maturation of precursor RNA species is coupled to RNA polymerase II transcription. Co-transcriptional RNA processing helps to ensure efficient and proper capping, splicing, and 3' end processing of different RNA species to help ensure quality control of the transcriptome. Many improperly processed transcripts are not exported from the nucleus, are restricted to the site of transcription, and are in some cases degraded, which helps to limit any possibility of aberrant RNA causing harm to cellular health. These critical quality control pathways are regulated by the highly dynamic protein-protein interaction network at the site of transcription. Recent work has further revealed the extent to which the processes of transcription and RNA processing and quality control are integrated, and how critically their coupling relies upon the dynamic protein interactions that take place co-transcriptionally. This review focuses specifically on the intricate balance between 3' end processing and RNA decay during transcription termination. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Processing > 3' End Processing RNA Processing > Splicing Mechanisms RNA Processing > Capping and 5' End Modifications.

Studies in the field of developmental biology aim to unravel how a fertilized egg develops into an adult organism and how proteins and other macromolecules work together during this process. With regard to protein function, most of the developmental studies have used genetic and RNA interference approaches, combined with biochemical analyses, to reach this goal. However, there always remains much room for interpretation on how a given protein functions, because proteins work together with many other molecules in complex regulatory networks and it is not easy to reveal the function of one given protein without affecting the networks. Likewise, it has remained difficult to experimentally challenge and/or validate the proposed concepts derived from mutant analyses without tools that directly manipulate protein function in a predictable manner. Recently, synthetic tools based on protein binders such as scFvs, nanobodies, DARPins, and others have been applied in developmental biology to directly manipulate target proteins in a predicted manner. Although such tools would have a great impact in filling the gap of knowledge between mutant phenotypes and protein functions, careful investigations are required when applying functionalized protein binders to fundamental questions in developmental biology. In this review, we first summarize how protein binders have been used in the field, and then reflect on possible guidelines for applying such tools to study protein functions in developmental biology. This article is categorized under:Technologies > Analysis of ProteinsEstablishment of Spatial and Temporal Patterns > GradientsInvertebrate Organogenesis > Flies, Protein Quest: Guidelines for the use of protein binders in developmental biology.

The varied effects of recent extreme weather events around the world exemplify the uneven impacts of climate change on populations, even within relatively small geographic regions. Differential human vulnerability to environmental hazards results from a range of social, economic, historical, and political factors, all of which operate at multiple scales. While adaptation to climate change has been the dominant focus of policy and research agendas, it is essential to ask as well why some communities and peoples are disproportionately exposed to and affected by climate threats. The cases and synthesis presented here are organized around four key themes (resource access, governance, culture, and knowledge), which we approach from four social science fields (cultural anthropology, archaeology, human geography, and sociology). Social scientific approaches to human vulnerability draw vital attention to the root causes of climate change threats and the reasons that people are forced to adapt to them. Because vulnerability is a multidimensional process rather than an unchanging state, a dynamic social approach to vulnerability is most likely to improve mitigation and adaptation planning efforts. This article is categorized under:Vulnerability and Adaptation to Climate Change > Values-Based Approach to Vulnerability and Adaptation.

Noncoding RNA plays an important role in all aspects of the cellular life cycle, from the very basic process of protein synthesis to specialized roles in cell development and differentiation. However, many noncoding RNAs remain uncharacterized and the function of most of them remains unknown. Mid-size noncoding RNAs (mncRNAs), which range in length from 50 to 400 nucleotides, have diverse regulatory functions but share many fundamental characteristics. Most mncRNAs are produced from independent promoters although others are produced from the introns of other genes. Many are found in multiple copies in genomes. mncRNAs are highly structured and carry many posttranscriptional modifications. Both of these facets dictate their RNA-binding protein partners and ultimately their function. mncRNAs have already been implicated in translation, catalysis, as guides for RNA modification, as spliceosome components and regulatory RNA. However, recent studies are adding new mncRNA functions including regulation of gene expression and alternative splicing. In this review, we describe the different classes, characteristics and emerging functions of mncRNAs and their relative expression patterns. Finally, we provide a portrait of the challenges facing their detection and annotation in databases. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.

Our present day understanding of nervous system development is an amalgam of insights gained from studying different aspects and stages of nervous system development in a variety of invertebrate and vertebrate model systems, with each model system making its own distinctive set of contributions. One aspect of nervous system development that has been among the most extensively studied in the nematode Caenorhabditis elegans is the nature of the gene regulatory programs that specify hardwired, terminal cellular identities. I first summarize a number of maps (anatomical, functional, and molecular) that describe the terminal identity of individual neurons in the C. elegans nervous system. I then provide a comprehensive summary of regulatory factors that specify terminal identities in the nervous system, synthesizing these past studies into a regulatory map of cellular identities in the C. elegans nervous system. This map shows that for three quarters of all neurons in the C. elegans nervous system, regulatory factors that control terminal identity features are known. In-depth studies of specific neuron types have revealed that regulatory factors rarely act alone, but rather act cooperatively in neuron-type specific combinations. In most cases examined so far, distinct, biochemically unlinked terminal identity features are coregulated via cooperatively acting transcription factors, termed terminal selectors, but there are also cases in which distinct identity features are controlled in a piecemeal fashion by independent regulatory inputs. The regulatory map also illustrates that identity-defining transcription factors are reemployed in distinct combinations in different neuron types. However, the same transcription factor can drive terminal differentiation in neurons that are unrelated by lineage, unrelated by function, connectivity and neurotransmitter deployment. Lastly, the regulatory map illustrates the preponderance of homeodomain transcription factors in the control of terminal identities, suggesting that these factors have ancient, phylogenetically conserved roles in controlling terminal neuronal differentiation in the nervous system. WIREs Dev Biol 2016, 5:474-498. doi: 10.1002/wdev.233 For further resources related to this article, please visit the WIREs website.

Viruses are obligatory intracellular parasites that require the host machinery to replicate. During their replication cycle, viral RNA intermediates can be recognized and degraded by different antiviral mechanisms that include RNA decay, RNA interference, and RNase L pathways. As a consequence of viral RNA degradation, infected cells can accumulate virus‐derived small RNAs at high levels compared to cellular molecules. These small RNAs are imprinted with molecular characteristics that reflect their origin. First, small RNAs can be used to reconstruct viral sequences and identify the virus from which they originated. Second, other molecular features of small RNAs such as size, polarity, and base preferences depend on the type of viral substrate and host mechanism of degradation. Thus, the pattern of small RNAs generated in infected cells can be used as a molecular footprint to identify and characterize viruses independent on sequence homology searches against known references. Hence, sequencing of small RNAs obtained from infected cells enables virus discovery and characterization using both sequence‐dependent strategies and novel pattern‐based approaches. Recent studies are helping unlock the full application of small RNA sequencing for virus discovery and characterization. WIREs RNA 2016, 7:824–837. doi: 10.1002/wrna.1361 This article is categorized under: 1RNA Processing > Processing of Small RNAs2RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms3RNA Methods > RNA Analyses In Vitro and In Silico

Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia-induced changes in the proteome mediated by the activity of transcription factors such as hypoxia-inducible factor 1. Hypoxia is a well-described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer-associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272-285. doi: 10.1002/wsbm.1334 For further resources related to this article, please visit the WIREs website.

Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro‐RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1‐S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical‐trial level. Our model allows for the inclusion of the unique molecular profiles of each individual patient's tumor. While existing clinical guidelines are well established, dynamic modeling may be used for future targeted combination therapies, which may progressively become part of clinical practice within the near future. WIREs Syst Biol Med 2016, 8:314–336. doi: 10.1002/wsbm.1342 This article is categorized under: 1Biological Mechanisms > Cell Signaling2Analytical and Computational Methods > Computational Methods3Translational, Genomic, and Systems Medicine > Translational Medicine

Most eukaryotic precursor mRNAs are subjected to RNA processing events, including 5′‐end capping, splicing and 3′‐end processing. These processing events were historically studied independently; however, since the early 1990s tremendous efforts by many research groups have revealed that these processing factors interact with each other to control each other's functions. U1 snRNP and its components negatively regulate polyadenylation of precursor mRNAs. Importantly, this function is necessary for protecting the integrity of the transcriptome and for regulating gene length and the direction of transcription. In addition, physical and functional interactions occur between splicing factors and 3′‐end processing factors across the last exon. These interactions activate or inhibit splicing and 3′‐end processing depending on the context. Therefore, splicing and 3′‐end processing are reciprocally regulated in many ways through the complex protein–protein interaction network. Although interesting questions remain, future studies will illuminate the molecular mechanisms underlying the reciprocal regulation. WIREs RNA 2016, 7:499–511. doi: 10.1002/wrna.1348 For further resources related to this article, please visit the WIREs website.

Spliceosome-mediated RNA trans-splicing, or SMaRT, is a promising strategy to design innovative gene therapy solutions for currently intractable genetic diseases. SMaRT relies on the correction of mutations at the post-transcriptional level by modifying the mRNA sequence. To achieve this, an exogenous RNA is introduced into the target cell, usually by means of gene transfer, to induce a splice event in trans between the exogenous RNA and the target endogenous pre-mRNA. This produces a chimeric mRNA composed partly of exons of the latter, and partly of exons of the former, encoding a sequence free of mutations. The principal challenge of SMaRT technology is to achieve a reaction as complete as possible, i.e., resulting in 100% repairing of the endogenous mRNA target. The proof of concept of SMaRT feasibility has already been established in several models of genetic diseases caused by recessive mutations. In such cases, in fact, the repair of only a portion of the mutant mRNA pool may be sufficient to obtain a significant therapeutic effect. However in the case of dominant mutations, the target cell must be freed from the majority of mutant mRNA copies, requiring a highly efficient trans-splicing reaction. This likely explains why only a few examples of SMaRT approaches targeting dominant mutations are reported in the literature. In this review, we explain in details the mechanism of trans-splicing, review the different strategies that are under evaluation to lead to efficient trans-splicing, and discuss the advantages and limitations of SMaRT. WIREs RNA 2016, 7:487-498. doi: 10.1002/wrna.1347 For further resources related to this article, please visit the WIREs website.

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease that has been associated with a diverse array of genetic changes. Prominent among these are mutations in RNA-binding proteins (RBPs) or repeat expansions that give rise to toxic RNA species. RBPs are additionally central components of pathologic aggregates that constitute a disease hallmark, suggesting that dysregulation of RNA metabolism underlies disease progression. In the context of neuronal physiology, transport of RNAs and localized RNA translation in axons are fundamental to neuronal survival and function. Several lines of evidence suggest that axonal RNA translation is a central process perturbed by various pathogenic events associated with ALS. Dysregulated translation of specific RNA groups could underlie feedback effects that connect and reinforce disease manifestations. Among such candidates are RNAs encoding proteins involved in the regulation of microtubule dynamics. Further understanding of axonally dysregulated RNA targets and of the feedback mechanisms they induce could provide useful therapeutic insights. WIREs RNA 2016, 7:589-603. doi: 10.1002/wrna.1352 For further resources related to this article, please visit the WIREs website.

Small RNAs and their associated RNA interference (RNAi) pathways underpin diverse mechanisms of gene regulation and genome defense across all three kingdoms of life and are integral to virus–host interactions. In plants, fungi and many animals, an ancestral RNAi pathway exists as a host defense mechanism whereby viral double‐stranded RNA is processed to small RNAs that enable recognition and degradation of the virus. While this antiviral RNAi pathway is not generally thought to be present in mammals, other RNAi mechanisms can influence infection through both viral‐ and host‐derived small RNAs. Furthermore, a burgeoning body of data suggests that small RNAs in mammals can function in a non‐cell autonomous manner to play various roles in cell‐to‐cell communication and disease through their transport in extracellular vesicles. While vesicular small RNAs have not been proposed as an antiviral defense pathway per se, there is increasing evidence that the export of host‐ or viral‐derived RNAs from infected cells can influence various aspects of the infection process. This review discusses the current knowledge of extracellular RNA functions in viral infection and the technical challenges surrounding this field of research. This article is categorized under:Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAsRNA in Disease and Development > RNA in DiseaseRegulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action