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.
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.
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.
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
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.
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.
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.
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.
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
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
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.
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.
10/24
Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment (Science 2022 MPI Melina Schuh)
Mammalian oocytes stop transcription during later stages of growth and do not turn it back on until the embryonic genome is activated after fertilization - Thus, oocyte development into a mature egg occurs without transcription.
During this process, the oocyte must rely on previously stored mRNA to translate the new protein
Previous studies have identified various types of mRNA-storing membraneless compartments in non-mammalian oocytes. However, it is unclear where and how mRNA is stored in mammalian oocytes.
This paper finds that mammalian oocytes store mRNA in a mitochondria-associated membraneless compartment
The researchers identified RNA-binding proteins highly expressed in the cytoplasm of mouse oocytes by mass spectrometry and analyzed the localization of these proteins by immunostaining. These proteins were found to aggregate near mitochondria and form clusters with mitochondria.
In contrast, these RNA-binding proteins did not co-localize with other organelles, or only partially co-localized. RNA in situ hybridization (RNA-FISH) experiments revealed that mRNA was also localized in this structure, suggesting that it is an mRNA reservoir. Because this structure is significantly different from previously discovered RNA storage compartments, the researchers named the structure the mitochondria-associated ribonucleoprotein domain, or MARDO for short.
Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment (Science 2022 MPI Melina Schuh)
Mammalian oocytes stop transcription during later stages of growth and do not turn it back on until the embryonic genome is activated after fertilization - Thus, oocyte development into a mature egg occurs without transcription.
During this process, the oocyte must rely on previously stored mRNA to translate the new protein
Previous studies have identified various types of mRNA-storing membraneless compartments in non-mammalian oocytes. However, it is unclear where and how mRNA is stored in mammalian oocytes.
This paper finds that mammalian oocytes store mRNA in a mitochondria-associated membraneless compartment
The researchers identified RNA-binding proteins highly expressed in the cytoplasm of mouse oocytes by mass spectrometry and analyzed the localization of these proteins by immunostaining. These proteins were found to aggregate near mitochondria and form clusters with mitochondria.
In contrast, these RNA-binding proteins did not co-localize with other organelles, or only partially co-localized. RNA in situ hybridization (RNA-FISH) experiments revealed that mRNA was also localized in this structure, suggesting that it is an mRNA reservoir. Because this structure is significantly different from previously discovered RNA storage compartments, the researchers named the structure the mitochondria-associated ribonucleoprotein domain, or MARDO for short.
10/24
Differential mosquito attraction to humans is associated with skin-derived carboxylic acid levels (2022 Cell Rockefeller University Leslie B. Vosshall)
The paper found that some people are more attractive to mosquitoes due to different skin odors.
These people have higher levels of carboxylic acids on their skin, and mosquitoes with deficient sense of smell will show a decrease in preference, but they still can distinguish people with highly attracted odor and non-attractive odor.
Differential mosquito attraction to humans is associated with skin-derived carboxylic acid levels (2022 Cell Rockefeller University Leslie B. Vosshall)
The paper found that some people are more attractive to mosquitoes due to different skin odors.
These people have higher levels of carboxylic acids on their skin, and mosquitoes with deficient sense of smell will show a decrease in preference, but they still can distinguish people with highly attracted odor and non-attractive odor.
10/24
An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice (2022 Science Holly A. Ingraham Ajay Chawla)
Compared with premenopausal women, men are more likely to suffer from abnormal accumulation of liver fat, non-alcoholic fatty liver disease, liver fibrosis and liver tumors
Sex differences in hepatic gene expression are regulated by transient secretion patterns of pituitary growth hormone
BCL6 is a class of sex-dependent, growth hormone-regulated hepatocyte transcription factors.
The paper found that BCL6 played a role in promoting the phenotype that male mice are more susceptible to high-fat diet-induced nonalcoholic fatty liver disease
In the case of bacterial infection, BCL6 can increase male survival rate, which is an evolutionary trade-off.
An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice (2022 Science Holly A. Ingraham Ajay Chawla)
Compared with premenopausal women, men are more likely to suffer from abnormal accumulation of liver fat, non-alcoholic fatty liver disease, liver fibrosis and liver tumors
Sex differences in hepatic gene expression are regulated by transient secretion patterns of pituitary growth hormone
BCL6 is a class of sex-dependent, growth hormone-regulated hepatocyte transcription factors.
The paper found that BCL6 played a role in promoting the phenotype that male mice are more susceptible to high-fat diet-induced nonalcoholic fatty liver disease
In the case of bacterial infection, BCL6 can increase male survival rate, which is an evolutionary trade-off.
10/25
Tissue-specific Grb10/Ddc insulator drives allelic architecture for cardiac development (2022 Molecular Cell Upenn Marisa S. Bartolomei)
Diploid organisms have two sets of chromosomes, one from each parent.
In mammals, there are about 200 genes called imprinted genes that express genes from only one parent. These imprinted genes in the germline carry DNA methylation memory from the parent.
These imprinted genes in the germline carry DNA methylation memories from their parents.
DNA methylation-marked regions are also known as imprinting control regions (ICRs)
In addition to being a marker of parental memory, ICRs also control the expression of imprinted genes by coordinating, for example, noncoding RNAs and enhancers.
This paper identifies an unconventional differentially methylated region (DMRs) as a specific mechanism by which Grb10 and Ddc imprinted gene insulators regulate cardiac and muscle development.
Tissue-specific Grb10/Ddc insulator drives allelic architecture for cardiac development (2022 Molecular Cell Upenn Marisa S. Bartolomei)
Diploid organisms have two sets of chromosomes, one from each parent.
In mammals, there are about 200 genes called imprinted genes that express genes from only one parent. These imprinted genes in the germline carry DNA methylation memory from the parent.
These imprinted genes in the germline carry DNA methylation memories from their parents.
DNA methylation-marked regions are also known as imprinting control regions (ICRs)
In addition to being a marker of parental memory, ICRs also control the expression of imprinted genes by coordinating, for example, noncoding RNAs and enhancers.
This paper identifies an unconventional differentially methylated region (DMRs) as a specific mechanism by which Grb10 and Ddc imprinted gene insulators regulate cardiac and muscle development.
10/26
Time-restricted feeding mitigates obesity through adipocyte thermogenesis (2022 Science Joseph Bass Northwest University)
Excessive consumption of food is also associated with disturbances in the meal timing and metabolic cycle of one's own biological clock, that is, eating at inappropriate times is more likely to lead to fat accumulation.
Genetically induced disruption of the circadian clock can cause nocturnal animals to consume more food in the day time (dormancy period) and produce more severe obesity problems
Eating at the wrong time worsens food-induced obesity. But limiting high-calorie food to periods of activity can improve metabolism and support health.
This paper reports that the circadian rhythm negatively regulates the transcription factor, ZFP423, through thermogenesis. ZFP423 regulates creatine content in adipose tissue, and creatine content promotes ineffective creatine cycle to further regulate thermogenesis; ultimately regulates energy metabolism under a high-fat diet.
Time-restricted feeding mitigates obesity through adipocyte thermogenesis (2022 Science Joseph Bass Northwest University)
Excessive consumption of food is also associated with disturbances in the meal timing and metabolic cycle of one's own biological clock, that is, eating at inappropriate times is more likely to lead to fat accumulation.
Genetically induced disruption of the circadian clock can cause nocturnal animals to consume more food in the day time (dormancy period) and produce more severe obesity problems
Eating at the wrong time worsens food-induced obesity. But limiting high-calorie food to periods of activity can improve metabolism and support health.
This paper reports that the circadian rhythm negatively regulates the transcription factor, ZFP423, through thermogenesis. ZFP423 regulates creatine content in adipose tissue, and creatine content promotes ineffective creatine cycle to further regulate thermogenesis; ultimately regulates energy metabolism under a high-fat diet.
10/27
CRISPR/Cas9-induced structural variations expand in T lymphocytes in vivo (2022 Nucleic Acids Research 胡家志/徐墨 Peking/Tsinghua)
CRISPR-Cas gene editing tools are widely used in scientific research and clinical practice. However, in addition to on-target products and off-target editing, CRISPR-Cas also produces chromosomal structural variations (SVs) such as chromosomal translocations and large deletions, as well as massive viral DNA insertion
This paper uses the high-throughput sequencing method PEM-seq (primer-extension-mediated sequencing) to sensitively track chromosomal structural abnormalities and the fate of viral DNA insertions in CRISPR-Cas9 edited T cells after infusion into mice.
Among 16 mice infused with edited T-cells, two of them were found with significant expansion of T-cell monoclonals.
CRISPR/Cas9-induced structural variations expand in T lymphocytes in vivo (2022 Nucleic Acids Research 胡家志/徐墨 Peking/Tsinghua)
CRISPR-Cas gene editing tools are widely used in scientific research and clinical practice. However, in addition to on-target products and off-target editing, CRISPR-Cas also produces chromosomal structural variations (SVs) such as chromosomal translocations and large deletions, as well as massive viral DNA insertion
This paper uses the high-throughput sequencing method PEM-seq (primer-extension-mediated sequencing) to sensitively track chromosomal structural abnormalities and the fate of viral DNA insertions in CRISPR-Cas9 edited T cells after infusion into mice.
Among 16 mice infused with edited T-cells, two of them were found with significant expansion of T-cell monoclonals.