9/30
Reconstitution of a microtubule plus-end tracking system in vitro (Nature 2007 European Molecular Biology Laboratory Thomas Surrey)
EB1 homologue Mal3 has an enhanced affinity for growing microtubule end structures as opposed to the microtubule lattice
Mal3 acts as a factor that mediates loading of the processive motor Tea2 and its cargo, the Clip170 homologue Tip1, onto the microtubule lattice
+TIPs - highly conserved microtubule-associated proteins accumulates selectively at growing microtubule plus ends in living cells: CLIP-770; APC, EB1, ​​CLASPs, p150, and spectraplakins.
multiple aspects of cellular organization depend on a defined distribution of microtubules - the distribution is mediated by three +TIPs: the EB1 homologue Mal3, the Clip170 homologue Tip1 and the kinesin Tea2
the motor Tea2 and its putative cargo Tip1 move along the microtubule lattice towards its growing plus ends, where they accumulate
the motor Tea2 and its putative cargo Tip1 move along the microtubule lattice towards its growing plus ends, where they accumulate
Only one of the three proteins, the EB1 homologue Mal3, was able to bind efficiently to dynamic microtubules in the absence of the others.
This suggests that microtubule ends are decorated with Mal3 for a characteristic time of about 8 s, independently of microtubule growth velocity
In contrast to Mal3, green fluorescent protein (GFP)-tagged Tip1 and Alexa 488-labelled Tea2 did not bind significantly to the microtubules in conditions under which selective end tracking of Mal3 was observed
Mal3, Tea2 and Tip1 exist as a stable ternary complex

10/3
Spatial engineering of E. coli with addressable phase-separated RNAs (Cell 2022 France Haotian Guo)
Synthetic organelle realized in bacteria for the first time
membraneless organelles - Based on random interactions, specific biological macromolecules will undergo a physical process of liquid phase separation when they are in a critical state, thereby forming biomolecular condensate.
Problem: The internal physicochemical environment of bacteria and eukaryotic cells is very different, and the proteins of eukaryotic membraneless organelles can easily form solid precipitates in bacteria.
RNA can also phase separate independently
The team designed an RNA molecular architecture, Transcriptionally Engineered Addressable RNA Solvents (TEARS), for the realization of synthetic organelles, and confirmed that this is a modular and programmable condensate through transmission electron microscopy, fluorescence imaging, mRNA translation and other means.

Inclusion bodies, which are common in bacterial physiology, may have had their physical characteristics misestimated, and most likely also have fluid properties and thus enable complex biochemical processes.
In the past, it was believed that multilayer phase-separated structures such as the nucleolus required a variety of phase-separable proteins that interacted orthogonally to each other (Feric, Marina, et al. Cell 2016); however, the authors found that in many In a system where components interact, as long as one molecule can achieve phase separation, it is possible to produce a multi-layered separation structure.
In the scaffold-client model of equilibrium physics (Banani, Salman F., et al. Cell 166.3 2016), the selectivity of aggregates for recruiting proteins is determined by their composition, that is, the proportion of various "vacancies" However, the authors constructed a "ligand-receptor" theoretical model and experimentally proved that in the non-equilibrium state, the recruitment preference of condensates can be jointly controlled by rate constants such as binding and dilution.

Two different microtubule-based motor
activities with opposite polarities
in kinetochores
(傻逼Tim mitchison 啥都不写清楚啊啊啊啊啊啊我大哭

10/4
Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts (Nature 1996 Rebecca Heald)
Bipolar spindles can assemble in the absence of centrosomes and kinetochores - spindles form in the absence of centrosomes by motor-dependent sorting of microtubules according to their polarity
dynein is required for focusing microtubules into poles, but not for bundling into longitudinal arrays

10/4
Pitx2 patterns an accelerator-brake mechanical feedback through latent TGFb to rotate the gut (Science 2022 Natasza A. Kurpios Cornell)
In healthy embryos, the rotation of the gut is predictable, the gut is always counterclockwise and highly synergistic in time and space
Torsion of the gut requires the guidance of the transcription factor Pitx2
During the torsion of intestinal asymmetric development, the TGFbeta signaling pathway feeds back mechanical forces, driving Pitx2 to control the left transcriptional program in the dorsal mesentery, and the expression of Bmp4 on the right to accelerate the intestinal torsion process.

10/4
Condensed-phase signaling can expand kinase specificity and respond to macromolecular crowding (Molecular Cell 2022 Liam J.Holt NYC & Markus Zweckstetter MPI)
Phase separation can concentrate biomolecules and accelerate biochemical reactions
The complex cellular environment strongly influences phase separation, and the crowded and active internal biophysical environment of cells may be able to convert condensed biomolecular information into chemical signals, such as protein phosphorylation, etc.
In this paper, the authors use synthetic biology to demonstrate that phase-separated biomolecular condensates can enhance kinase signaling, more conducive to systematically improving signaling efficiency and responding to biophysical signals.

10/5
Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals (Science 2022 Wieland B. Huttner MPI)
The evolutionary expansion of the cerebral cortex and the consequent increase in the number of neurons underlies cognitive enhancement in human evolution
Endoscopic analysis revealed that modern humans had brain volumes similar to those of Neanderthals, suggesting that their brain volumes and cerebral cortex were similar in size.
It is found that a single amino acid of TKTL1 of the transketolase family has important differential effects on activity on large-scale neurogenesis in modern and ancient humans
There are two main types of neural progenitor cells in the developing cerebral cortex, called apical progenitors (APs) and basal progenitors (BPs), respectively.
TKTL1:
TKTL1 is preferentially expressed in neural progenitor cells of the cerebral cortex
TKTL1 is associated with human tumors and tumor cell proliferation and may increase the number of neural progenitor cells
TKTL1 is one of the few proteins with amino acid substitutions
The authors' work found that the expression of TKTL1 in the human cerebral cortex is particularly high in the frontal lobe of the developing brain, and the single amino acid activity of hTKTL1 promotes the abundance of basal neural progenitor cells in the frontal lobe of the brain, promoting the production of more modern human cerebral cortex of neurons.
The function of hTKTL1 is dependent on the pentose phosphate pathway and fatty acid synthesis, and inhibition of these metabolic pathways reduces the abundance of bRG in fetal human neocortex.

10/7
Chromatin jets define the properties of cohesin-driven in vivo loop extrusion (Molecular Cell 2022 UK)
During the interphase of cell division, the distribution of DNA in the nucleus is in units of chromosomes, and DNA of the same chromosome always tends to cluster together in three-dimensional space, a phenomenon known as Chromosome Territories
There is compartmentalization within chromosomes, namely compartment A (corresponding to transcriptionally active euchromatin) and compartment B (corresponding to inactive heterochromatin). Chromosomes in compartment A prefer to interact with chromosomes in compartment A. Chromosomes in compartment B also prefer to interact with chromosomes in compartment B. Chromatin topological domains (Topologically Associating Domains, TADs) are also a major chromatin interaction mode within chromosomes, which are mainly composed of 3D molecules such as Cohesin (a giant circular protein complex) and CTCF (CCCTC Binding Factor). Genome-building protein-mediated.
It is currently believed that Cohesin mediates genome-wide chromatin interactions through DNA loop extrusion. Cohesin-mediated DNA circularization can be anchored at the binding sites of transcription factors such as CTCF. On the one hand, it mediates specific chromatin interactions. Actions, including enhancer-promoter interactions, on the other hand prevent unnecessary chromatin interactions and function as transcriptional insulation. However, due to technical limitations, we still cannot directly observe the ongoing DNA circularization at the single-molecule level in vivo, and cannot determine the key features of the Cohesin-mediated DNA ring extrusion model, or even whether the model actually exists in vivo.
This paper observes the phenomenon of chromatin "jetting" (Chromatin Jets) in vivo, which provides important in vivo evidence and key parameters for the Cohesin-mediated DNA loop extrusion model.

10/7
Artificial intelligence finds faster algorithms for multiplying matrices (This is a summary of: Fawzi, A. et al. Discovering faster matrix multiplication algorithms with reinforcement learning. Nature 610, 47–53 (2022).)
It’s fast.
It could be even faster in the future.

10/7
Two different microtubule-based motor activities with opposite polarities in kinetochores (Nature 1991 Tim Mitchison)
kinetochores contain two motors, which move microtubules in an ATP-dependent manner, but which have opposite polarities.
The activities of these two motors can be regulated by factors that can influence phosphorylation.

10/10
Super-enhancers conserved within placental mammals maintain stem cell pluripotency (2022 PNAS China)
Super-enhancer (SE) is considered to be the main regulatory center of cell fate determination, maintenance of pluripotency and disease occurrence.
This study revealed that most of the super-enhancers have undergone rapid evolution in mammals through a systematic comparison of super-enhancers in humans, pigs and mice through multi-omics techniques, and identified 3 maintenance of SOX2, PIM1 and FGFR1 A key super-enhancer for pluripotency in placental mammals.

10/11
Sex- and age-dependent genetics of longevity in a heterogeneous mouse population (Science 2022 Johan Auwerx/ Robert W. Williams)
Through large-scale screening of longevity genes in mice, sex-specific and age-specific longevity loci have been discovered
Female mice live longer than males & Male mice have higher early mortality, mid-term females have higher mortality, and late-stage mortality is similar in both sexes - Genetic loci for longevity may be age-specific as well as sex-specific
The authors decided to validate the high-scoring longevity genes in C. elegans with a shorter life history and identified Hipk1, Ddost, Hspg2, Fgd6, and Pdk1 as candidate genes associated with longevity

10/11
Genetically encoded chemical crosslinking of RNA in vivo (Nat Chem 2022 Lei Wang UCSF)
The interaction of RNA with RNA-binding proteins (RBPs) is critical for almost all regulation on RNA.
Most of the existing methods use ultraviolet irradiation (Ultraviolet light, UV) to broad-spectrum crosslink to capture the interaction of intracellular RBPs and RNA.
At present, there is still a lack of technical means to achieve precise in vivo cross-linking and capture of RNA bound at RBP-specific sites (regions).
This article develops a novel genetic code expansion technology that enables precise cross-linking in vivo to capture RNA bound at RBP-specific sites (regions).
The traditional UV-mediated intracellular RBPs-RNA crosslinking strategy has been very successful in many studies, but it has several insurmountable shortcomings:
UV-mediated RBPs and RNA crosslinking have a strong nucleotide preference The vast majority of cross-linking occurs only between uracil (Uridine) and adjacent amino acids. If the region of the RNA bound by RBP lacks uracil, then the cross-linking and all subsequent experiments will not be successful.
Due to technical limitations, UV-mediated RNA-protein cross-linking is currently difficult to identify amino acid sites on proteins that specifically bind RNA.
In addition, the optical characteristics of UV make this cross-linking strategy basically unsuitable for in vivo studies of multicellular organisms.
Lei Wang's group developed a new genetically encoded chemical crosslinking technology named Genetically encoded chemical crosslinking of RNA in vivo (GECX-RNA) to achieve precise crosslinking in vivo to capture RBP RNA bound to a specific site (region)
GECX-RNA can insert latent bioreactive unnatural amino acids at different positions in RBPs through Genetic code expansion as needed.
RBPs inserted into such unnatural amino acids can specifically cross-link with nearby bound nucleotides through a proximity-enabled reactivity mechanism in vivo.
This technology can cross-link all four nucleotides while enabling precise cross-linking of RNA bound near the insertion site of unnatural amino acids. Moreover, the mechanism of proximity-enabled reactivity enables this technology to achieve in vivo cross-link capture without external triggers.

10/12
Inferring and perturbing cell fate regulomes in human brain organoids (Nature 2022)
Different neurons in the brain can develop from embryonic stem cells or induced pluripotent stem cells, and the fate and state of each different cell is the final result of complex regulation by different transcription factors.
Gene regulatory networks, GRNs
This paper enables the characterization of a comprehensive gene regulatory network in brain organoids by establishing a Pando analysis framework that integrates multi-omics data and transcription factor binding site prediction.

10/18
No role for nuclear transcription regulators in mammalian mitochondria? (Molecular Cell 2022 Nils-Goran Larsson Sweden)
Mitochondria - Most of the ATP required for cellular energy is produced by oxidative phosphorylation (OXPHOS)
In mammals, almost all mitochondrial proteins (>1100) are encoded in the nucleus, synthesized in the cytoplasm and imported, whereas only ~1% of mitochondrial proteins are encoded by the mitochondrial minigenome (mtDNA) and synthesized in the mitochondrial matrix.
In recent years, scholars have proposed that some factors that regulate nuclear transcription also exist in mammalian mitochondria and can directly regulate mtDNA transcription.
Challenge: Difficulty distinguishing indirect regulation of mtDNA transcription from altered nuclear gene expression from direct intramitochondrial effects
This article questioned the concept of direct regulation of mtDNA transcription by nuclear factors, assessed the role of intramitochondrial factors involved in the direct regulation of mammalian mtDNA transcription, and discussed in the light of the available evidence that factors that regulate nuclear transcription are unlikely to have any effect on the mitochondrial matrix to cause a direct impact on the mtDNA transcription machinery.

10/19
Actin maturation requires the ACTMAP/C19orf54 protease (Science 2022 Thijn R. Brummelkamp Netherlands)
The synthesis of proteins usually starts with methionine, which is removed during translation. But actin in cells does not follow this rule, because actin synthesis involves post-translational removal of acetylated methionine.
However, the protease that removes acetylated methionine remains unclear.
This paper proposed the specific molecular biological mechanism of C19orf54/ACTMAP actin maturation protease promoting actin maturation, regulating cytoskeletal organization, force generation and cell migration was determined by proteomic analysis.

10/19
Control of cell state transitions (Nature 2022 Boris N. Kholodenko)
The researchers constructed the cSTAR model (Cell state transition assessment and regulation) to distinguish cell states, quantify decision elements, reconstruct the network of mechanisms that control cell state transitions, and identify allowable manipulation of cell state transitions.
Cell states are switchable. However, understanding of how cellular networks drive cell state transitions and how cell states are purposefully manipulated and controlled is lacking
cSTAR model: is used to differentiate cellular states, quantify their determinants, reconstruct the network of mechanisms that control cellular state transitions, and identify changes in cellular states that can be identified
The construction of cSTAR needs

Efficiently separate data by clustering the data and constructing a "hyperplane that separates molecular features of cell states, maximizing the distance between data points belonging to different cell states"
Construct a state transition vector representing a path from one cell state center to another cell state center in molecular data space
Dynamic phenotypic characterization, quantifying phenotypic changes in cells in response to perturbation by measuring whether the perturbation shifts the state center toward or away from the hyperplane
Bayesian formulation for modular response analysis, reconstructing the topology, direction, and strength of causal connections between core network nodes created by components specified by state transition vectors
Computational mechanical models based on ordinary differential equations or stochastic differential equations

10/19
Maturation and circuit integration of transplanted human cortical organoids (Nature 2022 Sergiu P. Pașca Stanford)
Transplantation of human cortical organoids (hCO) into the rat brain allowed normal development, with neurons maturing and participating in circuit integration to control behavior.
This approach may be useful for clinical detection of circuit phenotypes in patient-derived cells.