
CRISPR revolutionized biology and medicine with gene editing technology. A novel ensemble learning method for sgRNA design improves accuracy and generalizability.


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CRISPR: Ensemble Model for sgRNA Design


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Lysosomal fission mechanisms are being uncovered.


Mechanism found that enables the fission of lysosomal organelles.

The race to uncover fission factors for lysosomal organelles heats up

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Chromatin interactions in ageing human brain cells impact gene expression and disease pathology.


We introduce multinucleic acid interaction mapping in single cells (MUSIC), for concurrent profiling of multiplex chromatin interactions, gene expression and RNA–chromatin associations within individual nuclei, as a tool for exploring chromatin architecture and transcription.

Single-cell multiplex chromatin and RNA interactions in ageing human brain - Nature

insights-into-chromatin-and-rna-interactions-in-ageing-human-brain


Insights into Chromatin and RNA Interactions in Ageing Human Brain



Efficient mRNA transcription termination is facilitated by the exoribonuclease Rat1 in eukaryotic organisms.


A study presents two cryo-EM structures of yeast Pol&nbsp;II pre-termination transcription complexes bound to Rat1–Rai1, and provides the mechanisms for termination of mRNA transcription in yeast and other eukaryotes.

Structural basis of exoribonuclease-mediated mRNA transcription termination - Nature

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Structural Mechanism of mRNA Transcription Termination by Exoribonuclease



HPO-27 and MROH1 are crucial for lysosome fission, maintaining lysosomal homeostasis and function.


The conserved HEAT repeat protein HPO-27 is identified as a lysosome scission factor in Caenorhabditis elegans, and the human homologue MROH1 also serves the same function to maintain lysosomal homeostasis.

The HEAT repeat protein HPO-27 is a lysosome fission factor - Nature

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Developing BundleTrac for efficient actin filament tracing in Stereocilia.


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Tracing and Segmentation of Actin Filaments in Stereocilia Using BundleTrac Algorithm



S-acylation of NLRP3 at Cys-130 controls Golgi access through a dynamic cycle.


NLRP3 is an inflammasome seeding pattern recognition receptor activated in response to multiple danger signals which perturb intracellular homeostasis. Electrostatic interactions between the NLRP3 polybasic (PB) region and negatively charged lipids on the trans-Golgi network (TGN) have been proposed to recruit NLRP3 to the TGN. In this study, we demonstrate that membrane association of NLRP3 is critically dependant on S-acylation of a highly conserved cysteine residue (Cys-130), which traps NLRP3 in a dynamic S-acylation cycle at the Golgi, and a series of hydrophobic residues preceding Cys-130 which act in conjunction with the PB region to facilitate Cys-130 dependent Golgi enrichment. Due to segregation from Golgi localised thioesterase enzymes caused by a nigericin induced breakdown in Golgi trafficking, NLRP3 becomes immobilised on the Golgi through reduced de-acylation of its Cys-130 lipid anchor, suggesting that disruptions in Golgi homeostasis are conveyed to NLRP3 through its acylation state. Thus, our work defines a nigericin sensitive S-acylation cycle that gates access of NLRP3 to the Golgi.

### Competing Interest Statement

The authors have declared no competing interest.

S-acylation of NLRP3 provides a nigericin sensitive gating mechanism that controls access to the Golgi

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NLRP3 S-acylation Mechanism for Golgi Access Control



Epithelial convergent extension results from the controlled transformation of internal force balance geometry.


Shape changes of epithelia during animal development, such as convergent extension, are achieved through concerted mechanical activity of individual cells. While much is known about the corresponding large scale tissue flow and its genetic drivers, key open questions regard the cell-scale mechanics, e.g. internal vs external driving forces, and coordination, e.g. bottom-up self-organization vs top-down genetic instruction. To address these questions, we develop a quantitative, model-based analysis framework to relate cell geometry to local tension in recently obtained timelapse imaging data of gastrulating Drosophila embryos. This analysis provides a systematic decomposition of cell shape changes and T1–rearrangements into internally driven, active, and externally driven, passive, contributions. Specifically, we find evidence that germ band extension is driven by active T1 processes that self-organize through positive feedback acting on tensions. More generally, our findings suggest that epithelial convergent extension results from controlled transformation of internal force balance geometry which we quantify with a novel quantification tool for local tension configurations.

### Competing Interest Statement

The authors have declared no competing interest.

The Geometric Basis of Epithelial Convergent Extension

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Epithelial Flow and Force-Balance Geometry Transformation



Gene regulatory networks and logic motifs play a crucial role in shaping cell fate decisions under different driving forces.


Organisms utilize gene regulatory networks (GRNs) to make fate decisions, but the regulatory mechanisms of transcription factors (TFs) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision- making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top- down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.

### Competing Interest Statement

The authors have declared no competing interest.

A Logic-incorporated Gene Regulatory Network Deciphers Principles in Cell Fate Decisions

deciphering-cell-fate-decisions-with-logic-incorporated-gene-regulatory-networks


Deciphering Cell Fate Decisions with Logic-Incorporated Gene Regulatory Networks



Circadian-regulated endocytic recycling is crucial for collagen fibril assembly, involving VPS33B and integrin α11 subunit.


Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin-α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33b secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33b led to loss of fibril rhythmicity and over-abundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33b and integrin-α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33b, integrin-α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.

### Competing Interest Statement

The authors have declared no competing interest.

Endocytic recycling is central to circadian collagen fibrillogenesis and disrupted in fibrosis

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The Role of Endosome in Collagen Fibril Assembly
