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Deploying anti-CRISPR proteins is a potent strategy used by phages to inhibit bacterial CRISPR-Cas defense. In a new Nature paper, Trost et al. 1 discover and characterize an exciting anti-CRISPR mechanism with possible implications beyond this microscopic arms race. Deploying anti-CRISPR proteins is a potent strategy used by phages to inhibit bacterial CRISPR-Cas defense. In a new Nature paper, Trost et al. discover and characterize an exciting anti-CRISPR mechanism with possible implications beyond this microscopic arms race. [ABSTRACT FROM AUTHOR]

The pre-fusion coronavirus HKU1 spike binds host sialoglycans and proteinaceous receptor TMPRSS2 for cell entry. In this issue of Cell , three papers by Fernández et al., McCallum et al., and Wang et al. provide structural information on HKU1 spike interactions with host receptors, providing insights into its multi-step opening. The pre-fusion coronavirus HKU1 spike binds host sialoglycans and proteinaceous receptor TMPRSS2 for cell entry. In this issue of Cell , three papers by Fernandez et al., McCallum et al., and Wang et al. provide structural information on HKU1 spike interactions with host receptors, providing insights into its multi-step opening. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature , Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDA receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature , Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDAR receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. [ABSTRACT FROM AUTHOR]

In their recent paper published in Nature , Luo et al. 1 investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias. In their recent paper published in Nature , Luo et al.1 investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias. [ABSTRACT FROM AUTHOR]

We talk to corresponding author Thomas Gonatopoulos-Pournatzis and co-first authors Arun Prasath Damodaran and Mei-Sheng Xiao about their paper "Genome-scale exon perturbation screens uncover exons critical for cell fitness" (in this issue of Molecular Cell) and get insights into their findings, career trajectories, and future directions in the pre-mRNA processing field. [ABSTRACT FROM AUTHOR]

In 1973, two papers from Bliss and Lømo and from Bliss and Gardner-Medwin reported that high-frequency synaptic stimulation in the dentate gyrus of rabbits resulted in a long-lasting increase in synaptic strength. This form of synaptic plasticity, commonly referred to as long-term potentiation (LTP), was immediately considered as an attractive mechanism accounting for the ability of the brain to store information. In this historical piece looking back over the past 50 years, we discuss how these two landmark contributions directly motivated a colossal research effort and detail some of the resulting milestones that have shaped our evolving understanding of the molecular and cellular underpinnings of LTP. We highlight the main features of LTP, cover key experiments that defined its induction and expression mechanisms, and outline the evidence supporting a potential role of LTP in learning and memory. We also briefly explore some ramifications of LTP on network stability, consider current limitations of LTP as a model of associative memory, and entertain future research orientations. Caya-Bissonnette and Béïque discuss the milestones that have shaped our current understanding of the molecular and cellular basis of long-term potentiation. [ABSTRACT FROM AUTHOR]

Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease. This paper establishes missense variants in the anoctamin family member ANO4 (or TMEM16D) as a cause of distinct epileptic disorders. Resulting phenotypes depend on the location in the protein and the functional impact of the substitution such as loss of cation channel function and increased apoptosis signaling. [ABSTRACT FROM AUTHOR]

Tardigrades withstand ionizing irradiation levels ∼500 times higher than humans can tolerate. Two recent papers shed light on how this might be achieved — via the transcriptional induction of DNA repair genes, the induction of a radioprotective DNA-binding protein, and possibly also the heightened capacity of repair proteins. [ABSTRACT FROM AUTHOR]

Sleep is a universal, essential biological process. It is also an invaluable window on consciousness. It tells us that consciousness can be lost but also that it can be regained, in all its richness, when we are disconnected from the environment and unable to reflect. By considering the neurophysiological differences between dreaming and dreamless sleep, we can learn about the substrate of consciousness and understand why it vanishes. We also learn that the ongoing state of the substrate of consciousness determines the way each experience feels regardless of how it is triggered—endogenously or exogenously. Dreaming consciousness is also a window on sleep and its functions. Dreams tell us that the sleeping brain is remarkably lively, recombining intrinsic activation patterns from a vast repertoire, freed from the requirements of ongoing behavior and cognitive control. The paper by Tononi et al. discusses what sleep reveals about the substrate of consciousness, how experience can vanish during sleep, and how dreams can be supported by a brain largely disconnected from the environment, unreflective, and forgetful. [ABSTRACT FROM AUTHOR]

Epigenetic inheritance of heterochromatin requires transfer of parental H3-H4 tetramers to both daughter duplexes during replication. Three recent papers exploit yeast genetics coupled to inheritance assays and AlphaFold2-multimer predictions coupled to biochemistry to reveal that a replisome component (Mrc1/CLASPIN) is an H3-H4 tetramer chaperone important for parental histone transfer to daughters. [ABSTRACT FROM AUTHOR]

Regenerative organisms such as plants must have specific signals that respond to damage and instruct remnant tissue to undergo repair. A recent paper identifies a long-sought candidate for the signal that links injury to regenerative programs. [ABSTRACT FROM AUTHOR]

In a recent paper in Nature , Petropoulos et al. 1 report that PARP1 acts together with the replisome components TIMELESS and TIPIN to protect the genome from transcription-replication conflicts, which has important implications for the clinical use of PARP inhibitors. In a recent paper in Nature , Petropoulos et al. report that PARP1 acts together with the replisome components TIMELESS and TIPIN to protect the genome from transcription-replication conflicts, which has important implications for the clinical use of PARP inhibitors. [ABSTRACT FROM AUTHOR]

We spoke with authors co-first authors Jayoung Ku, Keonyong Lee, and lead author Yoosik Kim about their paper "Alternative polyadenylation determines the functional landscape of inverted Alu repeats" (this issue of Molecular Cell), finding renewed energy from attending scientific meetings, and the open questions they are most interested in investigating next. [ABSTRACT FROM AUTHOR]

Understanding the evolution and subsequent maintenance of ecological diversity is a daunting task. Using a historical microbial evolution experiment, a new paper demonstrates the extent to which diversity can re-emerge in reduced communities and the traits through which rediversification occurs. [ABSTRACT FROM AUTHOR]

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes— CAMK2A, CAMK2B, CAMK2G , and CAMK2D —of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D , confirming an important role for the CAMK2D isozyme in both heart and brain function. CAMK2 disorder is a relatively new disorder where three of the four CAMK2s (CAMK2A, B, and G) are shown to cause neurodevelopmental disorders. In this paper we describe a cohort of eight individuals with neurodevelopmental disorders and cardiac abnormalities, having CAMK2D variants, proving all CAMK2s are important for normal development. [ABSTRACT FROM AUTHOR]

Distinguishing genomic alterations in cancer-associated genes that have functional impact on tumor growth and disease progression from the ones that are passengers and confer no fitness advantage have important clinical implications. Evidence-based methods for nominating drivers are limited by existing knowledge on the oncogenic effects and therapeutic benefits of specific variants from clinical trials or experimental settings. As clinical sequencing becomes a mainstay of patient care, applying computational methods to mine the rapidly growing clinical genomic data holds promise in uncovering functional candidates beyond the existing knowledge base and expanding the patient population that could potentially benefit from genetically targeted therapies. We propose a statistical and computational method (MAGPIE) that builds on a likelihood approach leveraging the mutual exclusivity pattern within an oncogenic pathway for identifying probabilistically both the specific genes within a pathway and the individual mutations within such genes that are truly the drivers. Alterations in a cancer-associated gene are assumed to be a mixture of driver and passenger mutations with the passenger rates modeled in relationship to tumor mutational burden. We use simulations to study the operating characteristics of the method and assess false-positive and false-negative rates in driver nomination. When applied to a large study of primary melanomas, the method accurately identifies the known driver genes within the RTK-RAS pathway and nominates several rare variants as prime candidates for functional validation. A comprehensive evaluation of MAGPIE against existing tools has also been conducted leveraging the Cancer Genome Atlas data. Cancer is known to arise after a cell experiences multiple driver mutations that allow it to grow uncontrollably and ultimately metastasize to distant anatomic sites. In this paper, we introduce a computational approach for identifying driver mutations by leveraging the mutual exclusivity of genes and variants within oncogenic pathways. [ABSTRACT FROM AUTHOR]

Mendelian randomization uses genetic variants as instrumental variables to make causal inferences on the effect of an exposure on an outcome. Due to the recent abundance of high-powered genome-wide association studies, many putative causal exposures of interest have large numbers of independent genetic variants with which they associate, each representing a potential instrument for use in a Mendelian randomization analysis. Such polygenic analyses increase the power of the study design to detect causal effects; however, they also increase the potential for bias due to instrument invalidity. Recent attention has been given to dealing with bias caused by correlated pleiotropy, which results from violation of the "instrument strength independent of direct effect" assumption. Although methods have been proposed that can account for this bias, a number of restrictive conditions remain in many commonly used techniques. In this paper, we propose a Bayesian framework for Mendelian randomization that provides valid causal inference under very general settings. We propose the methods MR-Horse and MVMR-Horse, which can be performed without access to individual-level data, using only summary statistics of the type commonly published by genome-wide association studies, and can account for both correlated and uncorrelated pleiotropy. In simulation studies, we show that the approach retains type I error rates below nominal levels even in high-pleiotropy scenarios. We demonstrate the proposed approaches in applied examples in both univariable and multivariable settings, some with very weak instruments. We propose a Bayesian framework for performing Mendelian randomization with potentially pleiotropic genetic instruments. Our proposed method, MR-Horse, is shown to produce unbiased causal effect estimates while avoiding inflated false positive rates, even with high levels of pleiotropy and weak instruments. We further extend the approach to the multivariable setting. [ABSTRACT FROM AUTHOR]

A new paper shows that rates of aggression are higher, and rates of coalition formation are lower, among male bonobos than among male chimpanzees. These findings are noteworthy because they challenge the view that female bonobos' preferences for less aggressive males favored a reduction in male aggression and an increase in social tolerance. [ABSTRACT FROM AUTHOR]

Bacterial genomes often harbor integrated viruses (prophages), which provide novel functions but also lyse cells under stressful conditions. A new paper combines mathematical models with experimental evolution to determine how prophages are maintained in bacterial populations despite their fitness costs. [ABSTRACT FROM AUTHOR]

In this issue of Molecular Cell , two papers provide insight into atypical structural maintenance of chromosomes protein complexes (SMCs). Jeppsson et al. 1 link Smc5/6 to supercoiled DNA, and Roisné-Hamelin et al. 2 show how Wadjet SMC bends and cleaves invading DNAs. In this issue of Molecular Cell , two papers provide insight into atypical structural maintenance of chromosomes protein complexes (SMCs). Jeppsson et al.1 link Smc5/6 to supercoiled DNA, and Roisné-Hamelin et al.2 show how Wadjet SMC bends and cleaves invading DNAs. [ABSTRACT FROM AUTHOR]

Post-translational modifications of proteins (PTMs) introduce an extra layer of complexity to cellular regulation. Although phosphorylation of serine, threonine, and tyrosine residues is well-known as PTMs, lysine is, in fact, the most heavily modified amino acid, with over 30 types of PTMs on lysine having been characterized. One of the most recently discovered PTMs on lysine residues is polyphosphorylation, which sees linear chains of inorganic polyphosphates (polyP) attached to lysine residues. The labile nature of phosphoramidate bonds raises the question of whether this modification is covalent in nature. Here, we used buffers with very high ionic strength, which would disrupt any non-covalent interactions, and confirmed that lysine polyphosphorylation occurs covalently on proteins containing PASK domains (polyacidic, serine-, and lysine-rich), such as the budding yeast protein nuclear signal recognition 1 (Nsr1) and the mammalian protein nucleolin. This Matters Arising Response paper addresses the Neville et al. (2024) Matters Arising paper, published concurrently in Molecular Cell. [Display omitted] [ABSTRACT FROM AUTHOR]

Molecular Cell speaks with first author Shouqiao Hou and corresponding author Daichao Xu about the scientific journey toward their paper, " PARP5A and RNF146 phase separation restrains RIPK1-dependent necroptosis " (in this issue of Molecular Cell), the challenges they faced, and interesting remaining questions for the field. [ABSTRACT FROM AUTHOR]

We spoke with co-corresponding authors Nico Wahl, Georg Dechant, and Galina Apostolova about their paper "SATB2 organizes the 3D genome architecture of cognition in cortical neurons" (this issue of Molecular Cell), their paths to a career in science, and the importance of perseverance. [ABSTRACT FROM AUTHOR]

We talk to Vasty Osei Amponsa and Kylie J. Walters about their paper " hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50 ", their journeys across continents leading them to the NCI, and how Kylie tries to foster curiosity and a sense of belonging in her lab. [ABSTRACT FROM AUTHOR]

We talk to first author Yuqiu Sun and corresponding author Hui Jiang about their paths in science, mentorship, and the exciting moments in the journey towards their paper "A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass" (this issue of Molecular Cell). [ABSTRACT FROM AUTHOR]

Molecular Cell talks with corresponding authors Steven West and Torben Heick Jensen about the journey toward back-to-back publication of their recent Molecular Cell papers, and they share their advice for coordinating the steps along the way. [ABSTRACT FROM AUTHOR]

We talk to first author Emily R. Feierman and corresponding author Erica Korb about the journey toward their paper "Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory" (this issue of Molecular Cell) and changes smoothing the road for women in science. [ABSTRACT FROM AUTHOR]

We talk to first author Laura Amaya about her paper "Pathways for macrophage uptake of cell-free circular RNAs" (in this issue of Molecular Cell), her path to becoming a scientist, and some of the lessons she's learned along the way. [ABSTRACT FROM AUTHOR]

In an interview with Dr. Mishtu Dey, Editor-in-chief of Cell Chemical Biology , two authors of the Technology article entitled "Facile generation of biepitopic antibodies with intrinsic agonism for activating tumor necrosis factor receptors"—Dr. Peter M. Tessier and Dr. Harkamal S. Jhajj—share more about their paper and their lives as scientists. [Display omitted] [ABSTRACT FROM AUTHOR]

In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology , the first and corresponding authors of the research article entitled " PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication " share insights on their paper and life as scientists. [ABSTRACT FROM AUTHOR]

We talk to first and last authors Guy Zoltsman and Rina Rosenzweig about their paper, "A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53," how every result may be important in the right context, and the importance to Rina that her lab is an encouraging and collaborative place. [ABSTRACT FROM AUTHOR]

The Mps1 and Aurora B kinases regulate and monitor kinetochore attachment to spindle microtubules during cell division, ultimately ensuring accurate chromosome segregation. In yeast, the critical spindle attachment components are the Ndc80 and Dam1 complexes (Ndc80c and DASH/Dam1c, respectively). Ndc80c is a 600-Å-long heterotetramer that binds microtubules through a globular "head" at one end and centromere-proximal kinetochore components through a globular knob at the other end. Dam1c is a heterodecamer that forms a ring of 16–17 protomers around the shaft of the single kinetochore microtubule in point-centromere yeast. The ring coordinates the approximately eight Ndc80c rods per kinetochore. In published work, we showed that a site on the globular "head" of Ndc80c, including residues from both Ndc80 and Nuf2, binds a bipartite segment in the long C-terminal extension of Dam1. Results reported here show, both by in vitro binding experiments and by crystal structure determination, that the same site binds a conserved segment in the long N-terminal extension of Mps1. It also binds, less tightly, a conserved segment in the N-terminal extension of Ipl1 (yeast Aurora B). Together with results from experiments in yeast cells and from biochemical assays reported in two accompanying papers, the structures and graded affinities identify a communication hub for ensuring uniform bipolar attachment and for signaling anaphase onset. • The kinase Mps1 binds the Ndc80 complex through a conserved motif • X-ray crystallography shows a common Ndc80c binding site for Mps1 and Dam1 • The Ipl1 N-terminal extension recognizes the Ndc80c site bound by Mps1 and Dam1 • Alphafold predictions suggest broad conservation of these shared interactions Zahm and Harrison combine binding studies and structure determinations to identify a common interaction site on the Ndc80 complex of yeast kinetochores for kinases Mps1 and Ipl1 and for the DASH subunit, Dam1. Sequences and alphafold predictions suggest a widely conserved regulatory hub on Ndc80c, consistent with data in accompanying articles. [ABSTRACT FROM AUTHOR]

Polyphosphate (polyP) is a chain of inorganic phosphate that is present in all domains of life and affects diverse cellular phenomena, ranging from blood clotting to cancer. A study by Azevedo et al. described a protein modification whereby polyP is attached to lysine residues within polyacidic serine and lysine (PASK) motifs via what the authors claimed to be covalent phosphoramidate bonding. This was based largely on the remarkable ability of the modification to survive extreme denaturing conditions. Our study demonstrates that lysine polyphosphorylation is non-covalent, based on its sensitivity to ionic strength and lysine protonation and absence of phosphoramidate bond formation, as analyzed via 31P NMR. Ionic interaction with lysine residues alone is sufficient for polyP modification, and we present a new list of non-PASK lysine repeat proteins that undergo polyP modification. This work clarifies the biochemistry of polyP-lysine modification, with important implications for both studying and modulating this phenomenon. This Matters Arising paper is in response to Azevedo et al. (2015), published in Molecular Cell. See also the Matters Arising Response by Azevedo et al. (2024), published in this issue. [Display omitted] • Lysine polyphosphorylation of Top1 and Nsr1 is a non-covalent modification • Lysine polyphosphorylation is ionic and sensitive to salt and protonation state • Lysine residues alone are sufficient for non-covalent polyP modification • Non-PASK yeast proteins undergo lysine-mediated non-covalent polyP modification Lysine polyphosphorylation was posited to be a covalent linkage of polyphosphate (polyP) to lysine sidechains within proteins. Neville et al. find that this modification is non-covalent and sensitive to ionic strength and alkaline pH. Lysine residues alone drive polyP modification via electrostatic interaction with polyP. [ABSTRACT FROM AUTHOR]

Transcription factors have proven difficult to target with small molecules because they lack pockets necessary for potent binding. Disruption of protein expression can suppress targets and enable therapeutic intervention. To this end, we developed a drug discovery workflow that incorporates cell-line-selective screening and high-throughput expression profiling followed by regulatory network analysis to identify compounds that suppress regulatory drivers of disease. Applying this approach to neuroblastoma (NBL), we screened bioactive molecules in cell lines representing its MYC-dependent (MYCNA) and mesenchymal (MES) subtypes to identify selective compounds, followed by PLATESeq profiling of treated cells. This revealed compounds that disrupt a sub-network of MYCNA-specific regulatory proteins, resulting in MYCN degradation in vivo. The top hit was isopomiferin, a prenylated isoflavonoid that inhibited casein kinase 2 (CK2) in cells. Isopomiferin and its structural analogs inhibited MYC and MYCN in NBL and lung cancer cells, highlighting the general MYC-inhibiting potential of this unique scaffold. [Display omitted] • OncoTreat prioritized subtype-selective compounds that disrupt a regulatory module • Top hits included prenylated isoflavonoid molecules that suppress MYCN protein • Pomiferin suppressed MYCN in vivo , slowing growth of SK-N-Be2 NBL xenografts • VIKING algorithm identified putative targets, including casein kinase2 (CK2) Stokes and Vasciaveo et al. evaluated selective agents targeting MYCN-amplified neuroblastoma cells using PLATE-Seq and regulatory network analysis. This revealed prenylated isoflavonoids that suppress a tumor checkpoint module, causing MYCN depletion and cell death. This paper highlights a multifaceted approach that enables screening for agents targeting networked drivers of disease. [ABSTRACT FROM AUTHOR]

In this editorial, Brian Plosky makes a distinction between retracting papers because of honest errors of interpretation and other types of retractions. [ABSTRACT FROM AUTHOR]

All-RNA-mediated targeted gene integration methods, rendering reduced immunogenicity, effective deliverability with non-viral vehicles, and a low risk of random mutagenesis, are urgently needed for next-generation gene addition technologies. Naturally occurring R2 retrotransposons hold promise in this context due to their site-specific integration profile. Here, we systematically analyzed the biodiversity of R2 elements and screened several R2 orthologs capable of full-length gene insertion in mammalian cells. Robust R2 system gene integration efficiency was attained using combined donor RNA and protein engineering. Importantly, the all-RNA-delivered engineered R2 system showed effective integration activity, with efficiency over 60% in mouse embryos. Unbiased high-throughput sequencing demonstrated that the engineered R2 system exhibited high on-target integration specificity (99%). In conclusion, our study provides engineered R2 tools for applications based on hit-and-run targeted DNA integration and insights for further optimization of retrotransposon systems., Competing Interests: Declaration of interests The authors have submitted patent applications based on the results reported in this paper. Q.Z. is a member of the Cell advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Artificial intelligence (AI) has profoundly advanced the field of biomedical research, which also demonstrates transformative capacity for innovation in drug development. This paper aims to deliver a comprehensive analysis of the progress in AI-assisted drug development, particularly focusing on small molecules, RNA, and antibodies. Moreover, this paper elucidates the current integration of AI methodologies within the industrial drug development framework. This encompasses a detailed examination of the industry-standard drug development process, supplemented by a review of medications presently undergoing clinical trials. Conclusively, the paper tackles a predominant obstacle within the AI pharmaceutical sector: the absence of AI-conceived drugs receiving approval. This paper also advocates for the adoption of large language models and diffusion models as a viable strategy to surmount this challenge. This review not only underscores the significant potential of AI in drug discovery but also deliberates on the challenges and prospects within this dynamically progressing field., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inference of causal transcriptional regulatory networks (TRNs) from transcriptomic data suffers notoriously from false positives. Approaches to control the false discovery rate (FDR), for example, via permutation, bootstrapping, or multivariate Gaussian distributions, suffer from several complications: difficulty in distinguishing direct from indirect regulation, nonlinear effects, and causal structure inference requiring "causal sufficiency," meaning experiments that are free of any unmeasured, confounding variables. Here, we use a recently developed statistical framework, model-X knockoffs, to control the FDR while accounting for indirect effects, nonlinear dose-response, and user-provided covariates. We adjust the procedure to estimate the FDR correctly even when measured against incomplete gold standards. However, benchmarking against chromatin immunoprecipitation (ChIP) and other gold standards reveals higher observed than reported FDR. This indicates that unmeasured confounding is a major driver of FDR in TRN inference. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests A.B. is a stockholder for Alphabet, Inc.; has consulted for Third Rock Ventures; and is a founder of CellCipher, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Single-cell transcriptomics reveals significant variations in transcriptional activity across cells. Yet, it remains challenging to identify mechanisms of transcription dynamics from static snapshots. It is thus still unknown what drives global transcription dynamics in single cells. We present a stochastic model of gene expression with cell size- and cell cycle-dependent rates in growing and dividing cells that harnesses temporal dimensions of single-cell RNA sequencing through metabolic labeling protocols and cel lcycle reporters. We develop a parallel and highly scalable approximate Bayesian computation method that corrects for technical variation and accurately quantifies absolute burst frequency, burst size, and degradation rate along the cell cycle at a transcriptome-wide scale. Using Bayesian model selection, we reveal scaling between transcription rates and cell size and unveil waves of gene regulation across the cell cycle-dependent transcriptome. Our study shows that stochastic modeling of dynamical correlations identifies global mechanisms of transcription regulation. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable population of proliferating unipolar brush cell progenitors in the mouse Atoh1 lineage, previously described in humans as the origin of one medulloblastoma subtype. Collectively, our data provide insights into the developing mouse hindbrain and markers for functional assessment of understudied neuronal populations., Competing Interests: Declaration of interests R.S.D. is a paid consultant for AstraZeneca. H.Y.Z. is a member of the Board of Regeneron, co-founder of Cajal Neuroscience, and on the science advisory board of the Column group. This is work in the Zoghbi Lab and has not been licensed anywhere. The work in this paper has no connection to any of the consulting or companies named here., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The outer hair cells (OHCs) of the mammalian cochlea are the mediators of an active, nonlinear electromechanical process necessary for sensitive, frequency-specific hearing. The membrane protein prestin conveys to the OHC a piezoelectric-like behavior hypothesized to actuate a high frequency, cycle-by-cycle conversion of electrical to mechanical energy to boost cochlear responses to low-level sound. This hypothesis has been debated for decades, with two key remaining issues: the influence of the rate dependence of conformal changes in prestin and the OHC transmembrane impedance. In this paper, we mainly focus on the rate dependence of the conformal change in prestin. A theoretical electromechanical model of the OHC that explicitly includes rate dependence of conformal transitions, viscoelasticity, and piezoelectricity. Using this theory, we show the influence of rate dependence and viscoelasticity on electromechanical force generation and transmembrane impedance. Furthermore, we stress the importance of using the correct mechanical boundary conditions when estimating the transmembrane capacitance. Finally, a set of experiments is described to uniquely estimate the constitutive properties of the OHC from whole-cell measurements., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The inhabitants of our intestines, collectively called the gut microbiome, comprise fungi, viruses, and bacterial strains. These microorganisms are involved in the fermentation of dietary compounds and the regulation of our adaptive and innate immune systems. Less known is the reciprocal interaction between the gut microbiota and type 2 diabetes mellitus (T2DM), as well as their role in modifying therapies to reduce associated morbidity and mortality. In this review, we aim to discuss the existing literature on gut microbial strains and their diet-derived metabolites involved in T2DM. We also explore the potential diagnostics and therapeutic avenues the gut microbiota presents for targeted T2DM management. Personalized treatment plans, driven by diet and medication based on the patient's microbiome and clinical markers, could optimize therapy., Competing Interests: Declaration of interests M.N. is a co-founder and member of the Scientific Advisory Board of Caelus Pharmaceuticals and Advanced Microbial Interventions, the Netherlands. None of these are directly relevant to the current paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

While horizontal basal cells (HBCs) make minor contributions to olfactory epithelium (OE) regeneration during homeostatic conditions, they possess a potent, latent capacity to activate and subsequently regenerate the OE following severe injury. Activation requires, and is mediated by, the downregulation of the transcription factor (TF) TP63. In this paper, we describe the cellular processes that drive the nascent stages of HBC activation. The compound phorbol 12-myristate 13-acetate (PMA) induces a rapid loss in TP63 protein and rapid enrichment of HOPX and the nuclear translocation of RELA, previously identified as components of HBC activation. Using bulk RNA sequencing (RNA-seq), we find that PMA-treated HBCs pass through various stages of activation identifiable by transcriptional regulatory signatures that mimic stages identified in vivo. These temporal stages are associated with varying degrees of engraftment and differentiation potential in transplantation assays. Together, these data show that our in vitro HBC activation system models physiologically relevant features of in vivo HBC activation and identifies new candidates for mechanistic testing., Competing Interests: Declaration of interests J.E.S. is a co-founder of Rhino Therapeutics, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Intestinal bacteria help keep humans healthy by regulating lipid and glucose metabolism as well as the immunological and neurological systems. Oral treatment using intestinal bacteria is limited by the high acidity of stomach fluids and the immune system's attack on foreign bacteria. Scientists have created coatings and workarounds to overcome these limitations and improve bacterial therapy. These preparations have demonstrated promising outcomes, with advances in synthetic biology and optogenetics improving their focused colonization and controlled release. Engineering bacteria preparations have become a revolutionary therapeutic approach that converts intestinal bacteria into cellular factories for medicinal chemical synthesis. The present paper discusses various aspects of engineering bacteria preparations, including wrapping materials, biomedical uses, and future developments., Competing Interests: Declaration of interests W.T. declares the following competing financial interest(s): W.T. receives consults (or on scientific advisory boards) for, lectured (and received a fee), or conducts sponsored research at Harvard Medical School/Brigham and Women’s Hospital for the following entities: Novo Nordisk A/S, Henlius USA Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concept of epigenetic therapy in humans. The premise is that epigenetic modulations could reactivate the repressed PWS candidate genes from the maternal chromosome and offer therapeutic benefit. Our prior study identifies an EHMT2/G9a inhibitor, UNC0642, that reactivates the expression of PWS genes via reduction of H3K9me2. However, low brain permeability and poor oral bioavailability of UNC0642 preclude its advancement into translational studies in humans. In this study, a newly developed inhibitor, MS152, modified from the structure of UNC0642, has better brain penetration and greater potency and selectivity against EHMT2/G9a. MS152 reactivated maternally silenced PWS genes in PWS patient fibroblasts and in brain and liver tissues of PWS mouse models. Importantly, the molecular efficacy of oral administration is comparable with the intraperitoneal route. MS152 treatment in newborns ameliorates the perinatal lethality and poor growth, maintaining reactivation in a PWS mouse model at postnatal 90 days. Our findings provide strong support for MS152 as a first-in-class inhibitor to advance the epigenetic therapy of PWS in humans., Competing Interests: Declaration of interests J.J. is a cofounder and equity shareholder in Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for Cullgen, Inc., EpiCypher, Inc., Accent Therapeutics, Inc, and Tavotek Biotherapeutics, Inc. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc., and Cullinan Oncology, Inc. Y.-H.J. is a co-founder of, has an equity interest in, is a scientific advisor to, and has an unpaid seat on the board of directors to Couragene, Inc., a biotechnology company that has licensed my intellectual property. However, Couragene did not have any direct role in this paper. J.J., Y.X., Y.-H.J., and S.W. are described in a patent application for MS1262 and MS152 as inventors, titled “G9A/GLP INHIBITORS AND METHODS OF USE” and “G9a/EHMT2 inhibitor use for Prader-Willi syndrome,” which were filed in the U.S. Patent and Trademark Office as application 63/515,010 (the “Application”)., (Copyright © 2024. Published by Elsevier Inc.)

Machine learning has the potential to be a powerful tool in the fight against antimicrobial resistance (AMR), a critical global health issue. Machine learning can identify resistance mechanisms from DNA sequence data without prior knowledge. The first step in building a machine learning model is a feature extraction from sequencing data. Traditional methods like single nucleotide polymorphism (SNP) calling and k-mer counting yield numerous, often redundant features, complicating prediction and analysis. In this paper, we propose PanKA, a method using the pangenome to extract a concise set of relevant features for predicting AMR. PanKA not only enables fast model training and prediction but also improves accuracy. Applied to the Escherichia coli and Klebsiella pneumoniae bacterial species, our model is more accurate than conventional and state-of-the-art methods in predicting AMR., Competing Interests: M.D.C., T.N., and H.A.N. are founders of AMROMICS JSC. H.S.N is a consultant to AMROMICS JSC., (© 2024 The Author(s).)

Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV) showed significantly enhanced antitumor activity in vivo compared with the noncovalent combination of UNE-C1 and E7. The combination of UCV with PD-1 blockades further augmented its therapeutic efficacy. Specifically, the conjugation of UNE-C1 to E7 enhanced its retention in inguinal draining lymph nodes, the specific delivery to dendritic cells and E7 antigen-specific T cell responses, and antitumor efficacy in vivo compared with the noncovalent combination of the two peptides. These findings suggest the potential of UNE-C1 derived from human cysteinyl-tRNA synthetase 1 as a unique vehicle for the specific delivery of cancer antigens to antigen-presenting cells via TLR2/6 for the improvement of cancer vaccines., Competing Interests: Declaration of interests S.K. is an inventor on patents 10-2022-0070287 related to this paper and is a founder of Zymedi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A recombinant lineage of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryoelectron microscopy (cryo-EM) structures of XBB.1.5, XBB.1.16, EG.5, and EG.5.1 spike (S) ectodomains to reveal reinforced 3-receptor binding domain (RBD)-down receptor-inaccessible closed states mediated by interprotomer RBD interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters, including stability, receptor binding, and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape., Competing Interests: Declaration of interests B.F.H., K.O.S., R.J.E., S.G., and P.A. are named in patents submitted on the SARS-CoV-2 monoclonal antibodies studied in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nitrogen doped carbon materials have been studied as catalyst support for ammonia decomposition. There are 4 different types of nitrogen environments (graphitic, pyrrolic, pyridinic and nitrogen oxide) on the amorphous support identified. In this paper, we report a 5%Ru on MgCO 3 pre-treated nitrogen doped carbon catalyst with high content of edge nitrogen-containing sites which displays an ammonia conversion rate of over 90% at 500°C and WHSV = 30,000 mL g cat -1 h -1 . It also gives an impressive hydrogen production rate of 31.3 mmol/(min g cat ) with low apparent activation energy of 43 kJ mol -1 . Fundamental studies indicate that the distinct average Ru-N 4 coordination site on edge regions is responsible for such high catalytic activity. Ammonia is stepwise decomposed via a Ru-N(H)-N(H)-Ru intermediate. This associative mechanism circumvents the direct cleavage of energetic surface nitrogen from metal to form N 2 hence lowering the activation barrier for the decomposition over this catalyst., Competing Interests: The authors declare no competing interests., (© 2024 Published by Elsevier Inc.)