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Новое в науке на 2022-12-08

Finding causal genes underlying risk for coronary artery disease

Previous genome-wide association studies of coronary artery disease (CAD) have discovered multiple susceptibility loci but have largely failed to uncover causal genes. A new study identifies hundreds of likely causal genes underlying the genetic risk for CAD.


Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Genome-wide association analyses, functionally informed fine-mapping and complementary gene prioritization approaches identify new risk loci and candidate effector genes for CAD.


Genomic innovation and regulatory rewiring during evolution of the cotton genus Gossypium

Pan-genome and pan-3D genome analyses of the Gossypium genus reveal evolutionary relationships among transposon-driven genome expansion and chromatin topology innovation and regulatory variations for cotton fiber development.


Identification of fish species through tRNA-based primer design

The correct establishment of the barcode classification system for fish can facilitate biotaxonomists to distinguish fish species, and it can help the government to verify the authenticity of the ingredients...


Identification of multiplicatively acting modulatory mutational signatures in cancer

A deep understanding of carcinogenesis at the DNA level underpins many advances in cancer prevention and treatment. Mutational signatures provide a breakthrough conceptualisation, as well as an analysis...


Genetic futurism

Large-scale genotyping and phenotyping efforts, including biobanks, have revolutionized our understanding of the genetic architecture of human traits and diseases. Years of ever-larger genome-wide association studies (GWAS) have produced a catalog of genetic variants that contribute to complex traits. A corollary of this research has been the development of personalized polygenic scores (PGS) or polygenic risk scores (PRS).


Deciphering the mechanical code of the genome and epigenome

Basu and colleagues comprehensively characterize how sequence and epigenetic modifications impact the local mechanical properties of DNA. The results suggest that DNA mechanics may have evolved to aid diverse DNA-deforming biological processes.


Structural insights into the regulation of Cas7-11 by TPR-CHAT

Here the authors use cryo-EM and biochemical analysis to show how the ancillary protein TPR-CHAT regulates the nuclease function of the CRISPR-guided nuclease Cas7-11.


Polarity of the CRISPR roadblock to transcription

Hall et al. discovered the molecular mechanism for the polarity of the CRISPR roadblock to transcription: RNA polymerase progression can collapse the R-loop formed by a bound dCas to allow read-through from the PAM-distal side. Guide RNA modifications allow modulation of the dCas R-loop stability.


Long-distance dependency combined multi-hop graph neural networks for protein–protein interactions prediction

Protein–protein interactions are widespread in biological systems and play an important role in cell biology. Since traditional laboratory-based methods have some drawbacks, such as time-consuming,...


Prediction of polyreactive and nonspecific single-chain fragment variables through structural biochemical features and protein language-based descriptors

Monoclonal antibodies (mAbs) have been used as therapeutic agents, which must overcome many developability issues after the discovery from in vitro display libraries. Especially, polyreactive mAbs can...


robustica: customizable robust independent component analysis

Independent Component Analysis (ICA) allows the dissection of omic datasets into modules that help to interpret global molecular signatures. The inherent randomness of this algorithm can be overcome by...


Mechanism of cyclic β-glucan export by ABC transporter Cgt of Brucella

This work provides molecular insights into the export of cyclic glucans by a bacterial ABC transporter. The findings expand our understanding of polysaccharide trafficking across bacterial membranes, as well as protein-sugar interactions in general.


Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade

Spurr et al. identify high pretreatment aneuploidy score as a potential biomarker in patients with NSCLC who benefit from concurrent radiation and immune checkpoint inhibition, in immunogenomic analysis of data from a phase I clinical trial.


Science in a post-Brexit gridlock

As the UK’s feud with the EU over their post-Brexit trade agreement continues, science must not become collateral damage.


A phase I/Ib trial and biological correlate analysis of neoadjuvant SBRT with single-dose durvalumab in HPV-unrelated locally advanced HNSCC

Karam and colleagues report a phase I/Ib trial in patients with HNSCC treated with neoadjuvant SBRT and anti-PD-L1, and perform high-dimensional analyses of immune correlates of response in the tissue microenvironment and peripheral blood.


Structural basis of SNAPc-dependent snRNA transcription initiation by RNA polymerase II

Rengachari et al. provide a structural investigation of Pol II initiation at snRNA gene promoters and find that the snRNA-activating protein complex enables DNA opening and transcription initiation independent of TFIIE and TFIIH in vitro.


Structural basis for NaV1.7 inhibition by pore blockers

The voltage-gated sodium channel NaV1.7 plays essential roles in pain sensation. The authors report cryo-EM structures of NaV1.7 in complexes with three pore blockers, elucidating distinct mechanisms of action of their modulation on NaV1.7.


A cFLIP-flop switch for senolysis

Persistent senescent cancer cells have tumor-promoting potential, making their selective elimination a prime therapeutic objective. The death receptor inhibitor cFLIP has now been shown to counter the susceptibility of senescent cells to DR5-mediated extrinsic apoptosis, which can be therapeutically exploited.


cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis

Bernards and colleagues identify cFLIP as a common dependency of cancer cells by conferring protection from senolytic-induced cell death. They nominate combination of DR5 activation and cFLIP suppression for enhanced killing of senescent cancer cells.


Structures of transcription preinitiation complex engaged with the +1 nucleosome

Cryo-EM structures of the transcription preinitiation complex in the presence of the +1 nucleosome show how the general transcription factor TFIIH can interact with the nucleosome at several positions.


A macrophage-activated abscopal effect

Combinations of immune-checkpoint blockade and radiotherapy to modulate antitumor immunity have mainly focused on manipulating T cells. A study now shows that combining radiotherapy with activation of macrophages yields potent, abscopal effects in mouse tumor models that may be ready for translation into early clinical trials.


Metabolic symbiosis in pancreatic cancer

Pancreatic ductal carcinoma exists within a heterogenous and complex microenvironment that imposes austere conditions with limited nutrient availability. Clonally separable neoplastic cell populations are now shown to segregate into two distinct metabolic configurations, facilitating symbiotic intratumoral crosstalk to support survival and growth.


Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect

Nishiga and colleagues show therapeutic efficacy for a combination of radiotherapy and CD47 blockade, which also elicits an abscopal effect mediated by macrophages migrating into non-irradiated tumor sites and phagocytosing cancer cells.


Structure determination of inactive-state GPCRs with a universal nanobody

Cryo-EM has facilitated structural studies of membrane proteins, but inactive GPCRs have remained inaccessible due to their small size. Robertson et al. demonstrate a common nanobody-based approach to streamline the determination of such structures.