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Новое в науке на 2022-08-11

Unlatching a window into the molecular landscape of prion toxicity

A study published in Nature Structural & Molecular Biology now unveils, at the atomic level, the initial mechanisms of prion toxicity, providing insights into the pathogenic mechanisms of a protein neurodegenerative disease caused by protein misfolding.


Filling in the blanks: how the C-strand catches up to the G-strand at replicating telomeres using CST

CST is both an ssDNA-binding complex and a DNA Pol-α/primase cofactor that coordinates the switch from G-strand elongation to C-strand fill-in during telomere maintenance. Four papers in Nature Structural & Molecular Biology and Nature provide transformative insights into CST activity, providing a platform to understand lagging-strand synthesis genome wide.


Conformational buffering underlies functional selection in intrinsically disordered protein regions

Foutel et. al. identify conformational buffering as a mechanism for functional selection in intrinsically disordered protein regions that allows robust encoding of a tethering function by a hypervariable disordered linker through compensatory changes in sequence length and composition.


A conformational switch controlling the toxicity of the prion protein

The H-latch is a well-defined structural change occurring in PrPC bound to the neurotoxic antibody POM1, and its presence shows a positive correlation with neurotoxicity. Inhibition of the H-latch prolongs the lifespan of prion-diseased mice.


Gene regulation on extrachromosomal DNA

Amplification of oncogene expression through extrachromosomal DNA is a common feature of many cancers and is associated with poor outcomes. Hung et al. review how regulation of extrachromosomal DNA gene expression is linked to alterations in chromatin structure and changes in contacts with DNA regulatory elements.


HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription

HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the BCL11A gene, a fetal globin repressor, by reducing chromatin accessibility and displacing the transcription factor GATA1.


cfDNA methylome profiling for detection and subtyping of small cell lung cancers

Dive and colleagues develop an approach for genome-wide cell-free DNA methylation profiling, which can sensitively detect small cell lung cancer in liquid biopsy of patient samples, including stage I disease and molecularly defined SCLC subtypes.


SMaSH: a scalable, general marker gene identification framework for single-cell RNA-sequencing

Single-cell RNA-sequencing is revolutionising the study of cellular and tissue-wide heterogeneity in a large number of biological scenarios, from highly tissue-specific studies of disease to human-wide cell...


Development and validation of the potential biomarkers based on m6A-related lncRNAs for the predictions of overall survival in the lung adenocarcinoma and differential analysis with cuproptosis

The treatment and prognosis of lung adenocarcinoma (LUAD) remains a challenge. The study aimed to conduct a systematic analysis of the predictive capacity of N6-methyladenosine (m6A)-related long non-coding...


TMbed: transmembrane proteins predicted through language model embeddings

Despite the immense importance of transmembrane proteins (TMP) for molecular biology and medicine, experimental 3D structures for TMPs remain about 4–5 times underrepresented compared to non-TMPs. Today’s top...


Risk score prediction model based on single nucleotide polymorphism for predicting malaria: a machine learning approach

The malaria risk prediction is currently limited to using advanced statistical methods, such as time series and cluster analysis on epidemiological data. Nevertheless, machine learning models have been...


ELIMINATOR: essentiality analysis using multisystem networks and integer programming

A gene is considered as essential when it is indispensable for cells to grow and replicate in a certain environment. However, gene essentiality is not a structural property but rather a contextual one, which...


Mapping the cancer cell states conserved across solid tumors

A new study uses single-cell and spatial transcriptomics to provide a systematic characterization of the recurrent gene-expression programs that control neoplastic cell states in diverse cancers.


Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment

Pan-cancer single-cell and spatial transcriptomic profiling identifies recurrent gene modules that underlie a continuum of cancer cell states. Tumor microenvironment influences the occurrence of these states.


Genetics of the human microglia regulome refines Alzheimer’s disease risk loci

Transcriptomic and epigenomic profiling of human microglia identifies putative gene regulatory mechanisms for 21 Alzheimer’s disease (AD) risk loci. SPI1/PU.1 is nominated as a key regulator of microglia gene expression and AD risk.


Molecular map of chronic lymphocytic leukemia and its impact on outcome

A genomic, transcriptomic and epigenomic analysis of chronic lymphocytic leukemia identifies genetic drivers and molecular subtypes associated with clinical outcomes.


Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder

Analyses of the polygenic architecture of childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder (ADHD) in a Danish population-based case–cohort sample identify differences among ADHD subgroups with respect to common and rare variants.


Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

A cross-ancestry genome-wide association meta-analysis of lung cancer including 61,047 cases and 947,237 controls identifies five new cross-ancestry susceptibility loci and highlights ancestry-specific effects of common and rare variants on lung cancer risk.


Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5

Xi and colleagues show that BMP signaling has tumor-suppressive effects in ACVR1 wild-type diffuse intrinsic pontine glioma by modulating stemness via chromatin regulation of CXXC5, and demonstrate the therapeutic potential of this pathway using in vivo mouse models.


Defending health rights in a post-Roe world

The US Supreme Court’s ruling to overturn Roe v. Wade will affect patients with cancer and cancer care providers across the United States. In this time of uncertainty, it is imperative to protect health rights and evidence-based care.


Hitting the target in HER2 mutant cancers

Though HER2 (ERBB2) exon 20 insertion mutations occur in ~2% of non-small-cell lung cancers, molecular targeted therapies for such cancers have been lacking. A study now identifies selective HER2 inhibitors that have marked efficacy against tumors driven by HER2 exon 20 insertions, without inhibiting wild-type EGFR activity.


PARP11 interfer(on)es with CAR T cell efficacy

Despite the remarkable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of hematological malignancies, this strategy remains challenging in solid tumors. One major obstacle is the hostile immunosuppressive tumor microenvironment. New research demonstrates that targeting PARP11 can overcome this immunosuppression and boost CAR T cell efficacy through stabilization of IFNAR1.


AKTing on XPO1 inhibition in AML

Inhibition of XPO1-mediated nuclear export by selinexor represents a promising therapeutic strategy in acute myeloid leukemia. Because XPO1 is not specific for tumor-suppressive proteins, selinexor may also activate pro-oncogenic processes. A study now shows that inhibition of selinexor-induced, purinergic receptor–mediated AKT activation potentiates its anti-leukemic activity.


Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Neumüller and colleagues identify and characterize potent HER2 exon 20 insertion-selective inhibitors with efficacy, which preserve wild-type epidermal growth factor receptor signaling in preclinical models of non-small cell lung cancer in vivo.