November 2022 Cell Journal Highlights

November 2022 is coming to an end, what are the highlights of the Cell journal in November that are worth learning? The editor has sorted out this and shared
it with you.

1.
Cell: The discovery of the CRISPR-Cas system in thousands of viruses promises to improve cell genome editing

doi:10.
1016/j.
cell.
2022.
10.
020

Systematic scanning of viral genomes reveals a plethora of potential CRISPR-based genome editing tools
.
The CRISPR-Cas system is common in the microbial world of bacteria and archaea that often help their host cells fight off viruses
.
But in a new study, researchers from the University of California, Los Angeles found that the CRISPR-Cas system accounts for 0.
4 percent
of the genome sequences of viruses known as bacteriophages that can infect these microbes.
They believe that the viruses use CRISPR-Cas to compete with each other--- and may also be manipulating the genetic activity of the host to their advantage
.
The results were published in the November 23, 2022 issue of Cell in the paper "Diverse virus-encoded CRISPR-Cas systems include streamlined genome editors
.
"

In the new study, Jennifer Doudna, a molecular biologist at the University of California, Berkeley, and Jillian Banfield, a microbiologist, and colleagues decided to look more holistically for the CRISPR-Cas system
in viruses that infect bacteria and archaea (i.
e.
, bacteriophages).
To their surprise, they found about 6,000 bacteriophages encoding the CRISPR-Cas system, including representatives of
every known type of CRISPR-Cas system.
Doudna said, "There is evidence that these CRISPR-Cas systems are useful for bacteriophages
.
”

The authors found widespread variation in the usual CRISPR-Cas structure, with some CRISPR-Cas systems missing components and others unusually compact
.
Anne Chevallereau, who studies phage ecology and evolution at the French National Center for Scientific Research, said, "Even though phage-encoded CRISPR-Cas systems are rare, they are highly diverse and widely distributed
.
Nature is full of surprises
.
”

2.
Cell: The risk of NAFLD/NASH associated with GCKR-rs1260326 mutation was revealed through liver organoids to be very high

doi:10.
1016/j.
cell.
2022.
09.
031

As we all know, background affects many areas
.
Now, in a new study, researchers from Tokyo Medical University in Japan and Cincinnati Children's Hospital Medical Center in the United States have found that a patient's health context --- a patient's other diseases — can determine whether a particular gene mutation is beneficial or harmful
.
They revealed a genetic mutation that has a controversial relationship with liver disease that carries varying degrees of risk
depending on whether the patient has diabetes.
The results were published in the October 27, 2022 issue of the journal Cell in the paper "En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH
.
"

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
09.
031
.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can progress to nonalcoholic steatohepatitis (NASH),
which involves fat accumulation, damage, and inflammation in the liver.
Known genetic variants explain only a fraction of the risk of having NAFLD/NASH, and scientists disagree
on the importance of certain mutations.

To better understand the role of GCKR-rs1260326 in NAFLD/NASH, the authors extracted cells from 24 donors and cultured them into tiny liver-like organs, known as liver organoids
.
They provide these liver organoids with extra fatty acids that can lead to fat accumulation, inflammation, and insulin resistance, traits that can be seen
in the livers of NASH patients.
They then closely analyzed the link
between genetic variation and liver organoid characteristics.

Corresponding author Takanori Takebe said, "These results are very clear
.
We found that the risk of NAFLD/NASH associated with the GCKR-rs1260326 mutation was very high in our liver organoid model, although it was rarely considered clinically significant
.
”

Liver organoids carrying two copies of the GCKR-rs1260326 mutation take up fat from their environment more efficiently than other liver organoids, which explains how this mutation can cause fatty liver
disease.

Unexpectedly, an analysis of real-life patient data showed that the level of liver inflammation in NASH patients with diabetes varied depending on the presence or absence of the mutation: diabetics who carried two copies of the mutated gene had high levels of liver inflammation, while diabetics without a copy of the mutated gene showed only low levels of liver inflammation
.

3.
Cell: New research has found a potent human IgM antibody against Zika virus infection

doi:10.
1016/j.
cell.
2022.
10.
023

In a new study, researchers from Weill Cornell Medical College in the United States, New York-Presbyterian Church, and the National Institutes of Health have discovered an unusual antibody type that neutralizes the Zika virus even at extremely small levels and makes this viral infection undetectable
in preclinical models 。 The results of the study were published online in the journal Cell on November 18, 2022, in the paper "A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization.
"

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
10.
023
.

In the new study, the authors used blood cells taken from pregnant women infected with Zika virus to isolate a super-strong immunoglobulin M (IgM) antibody--- a five-arm immune protein
that catches on to the virus.
In experiments on mice, they determined that the antibody not only protected them from deadly infections, but also suppressed the virus, making it undetectable
in the blood.

As it stands, doctors do not have approved vaccines or treatments available to patients
.
Dr.
Permar said that with further research, this antibody may help fill this gap
.
"It has two potential ways to use it: to rapidly reduce Zika virus levels in the blood of pregnant women who have been infected, or as a preventive measure, to those at risk of contracting the virus during
outbreaks.
"

4.
Cell: Chinese scientists revealed the molecular mechanism of human μ opioid receptor recognition of morphine and fentanyl

doi:10.
1016/j.
cell.
2022.
09.
041

In a new study, researchers from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, report and analyze the high-resolution cryo-electron microscopy (cryo-EM) structure of opioid analgesics such as fentanyl, morphine, and ollickeridine activated human μOR, revealing for the first time the mechanism
by which fentanyl and morphine induce μOR recognition and activation 。 The findings were published in the November 10, 2022 issue of the journal Cell under the title "Molecular recognition of morphine and fentanyl by the human μ-opioid receptor.
"

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
09.
041
.

The authors first obtained the three-dimensional structure
of human μOR when combined with equilibrium agonists (e.
g.
, fentanyl, morphine) and peptide Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO).
These agonists exhibit both G protein and arrestin signaling activity
.
They also resolved the three-dimensional structure
of μOR when combined with G protein-biased agonists such as TRV130, SR17018, and PZM21.
They then analyzed the signaling properties
of μOR under different signaling agonist activation through functional analysis and molecular dynamics simulations at the cellular level.
Their results showed that fentanyl occupies an extra binding pocket
around the outside of the cell TM2 and TM3 of μOR compared to morphine.

In addition, the aniline ring side chain of fentanyl forms a π-π hydrophobic interaction
with amino acid residues W295 and Y328.
Fentanyl's broader interaction with μOR results in fentanyl being 50-100 times
more potent than morphine.
Based on the structure of fentanyl-μOR-bound structure, these authors used molecular docking and mutagenesis studies to further explore the structure-activity relationship
between fentanyl and its derivatives and μOR.
They found that the potency of fentanyl and fentanyl analogues was highly correlated
with the varying degrees of interaction of these ligands with μOR amino acid residues such as D149, Y150, W135, and W320.

5.
Cell: New study reveals more than 5,000 essential genotypic maps in humans

doi:10.
1016/j.
cell.
2022.
10.
017

In a new study, researchers from the Whitehead Institute and the Broad Institute in the United States systematically evaluated the function of
more than 5,000 human-essential genes using a novel, ensemble, image-based screening method.
Their analysis leveraged CRISPR/Cas9 to knock out gene activity and formed a first-of-its-kind resource to understand and visualize the spatial and temporal resolution at which genes are observed across a range of cellular processes through spatial and temporal resolution
.
Their study covered more than 31 million cells and included hundreds of quantitative data on different parameters, enabling predictions of how genes would work and work
together.
The findings were published online on November 7, 2022 in the journal Cell under the title "The phenotypic landscape of essential human genes.
"

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
10.
017
.

Iain Cheeseman, co-corresponding author and a member of the Whitehead Institute, said, "Throughout my career, I've wanted to see what happens
in cells when the function of an essential gene is eliminated.
Today, we can do this, not just for one gene, but for every important gene in a human cell that splits in a petri dish, which is very powerful
.
The resources we create will benefit not only our own labs, but labs around the world
.
”

The authors evaluated the function of
5072 essential genes in a human cell line.
In this screening, they analyzed four markers --- DNA in these cells; DNA damage response, a key cellular pathway for detecting and responding to damaged DNA; Two important structural proteins: actin and tubulin
.

In addition to their initial screening, the authors conducted smaller follow-up screenings that focused on about 200 genes
involved in cell division, also known as "mitosis.
" These genes were identified in their initial screening as playing a definite role in mitosis, but had not previously been associated with
the process.
The data, available through a companion website called Vesuvius, provides a resource
for other scientists to study the function of the genes they are interested in.

6.
Cell: It was revealed that Helicobacter pylori uses the protein EgtUV to ingest the nutrient ergothioneine in food to resist oxidative stress

doi:10.
1016/j.
cell.
2022.
10.
008

In a new study, researchers from Yale University in the United States found that a nutrient commonly found in the human diet helps a cancer-causing bacterium survive
.
The discovery could reveal an important target for the development of new drugs
to treat many infectious diseases in humans.
The results of the study were published online in the journal Cell on November 7, 2022, in the paper "A microbial transporter of the dietary antioxidant ergothioneine.
"

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
10.
008
.

This nutrient, called ergothioneine (EGT), is a known antioxidant that has been found to protect bacteria from oxidative stress--- imbalance between reactive oxygen species (called free radicals) and antioxidants in the body, which is a feature of
many disease-causing infections.

Oxidative stress
occurs when immune cells produce oxygenated free radicals to kill harmful bacteria.
In this case, bacteria rely on antioxidant molecules that can fight free radicals produced by the immune system to survive
.
Despite decades of research, the specific molecules that certain bacteria use to defend against free radicals in our bodies remain a mystery
.

In response to this, the new study provides important clues
.
The authors found that bacteria ingest EGT, which is abundant in foods such as mushrooms, legumes and grains, to help them survive
.
In the case of Helicobacter pylori, the pathogen that causes stomach cancer, the bacteria use this nutrient to successfully compete for survival
in host tissues.

7.
Cell: Chinese scientists revealed the neural pathway of vomiting after eating infected food

doi:10.
1016/j.
cell.
2022.
10.
001

The urge to vomit after eating contaminated food is the body's natural defense response
to get rid of bacterial toxins.
However, the process by which our brains initiate this biological response after detecting germs remains elusive
.
In a new study, researchers from China's Beijing Institute of Life Sciences, Tsinghua University, Guangzhou Medical University, University of Science and Technology of China, Capital Medical University, and Fudan University have mapped for the first time detailed neural pathways
in mouse defense responses from the gut to the brain.
The discovery could help scientists develop better anti-nausea drugs
for cancer patients undergoing chemotherapy.
The findings were published in the November 10, 2022 issue of the journal Cell under the title "The gut-to-brain axis for toxin-induced defensive responses.
"

Co-corresponding author Peng Cao, Ph.
D.
, of the Beijing Institute of Life Sciences, and his team noted that while mice don't vomit, they gag--- meaning they also have the urge to vomit, but don't vomit
.
The team found that after receiving staphylococcal enterotoxin A (SEA), mice developed abnormal mouth opening, a common bacterial toxin produced by Staphylococcus aureus that also causes foodborne illness
in humans.

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
10.
001
.

Mice receiving SEA opened their mouths at a wider angle than was observed in control mice, which received saline
.
In addition, during mouth opening, the diaphragm muscles and abdominal muscles of the SEA-treated mice contracted simultaneously, a pattern
observed when dogs vomited.
During normal breathing, the animal's diaphragm muscles and abdominal muscles contract
alternately.

Cao said, "The neural mechanism of retching is similar
to the neural mechanism of vomiting.
In this experiment, we successfully established a model for studying toxin-induced retching in mice, through which we could study the brain's defense response
to toxins at the molecular and cellular levels.
”

In SEA-treated mice, the authors found that SEA in the gut activated enterochromaffin cells on the lining of the intestinal lumen to release the neurotransmitter serotonin
.
The released serotonin binds to receptors on vagus sensory neurons located in the gut, which carry these signals along the vagus nerve from the gut to specific types of neurons ----Tac1+DVC neurons
in the dorsal complex of the vagus nerve of the brainstem.
When Cao and his team inactivated Tac1+DVC neurons, SEA-treated mice had less
retching than mice with normal Tac1+ DVC neuronal activity.

In addition, the team investigated whether chemotherapy drugs activate the same neural pathways in which these drugs also induce defensive responses
such as nausea and vomiting in patients.
They injected mice with doxorubicin, a common chemotherapy drug
.
The drug made the mice gagg, but their retching behavior was significantly reduced
when they inactivated the release of serotonin from their Tac1+ DVC neurons or their enteric chromaffin cells.

8.
Cell: New method reveals that copy number variation has a powerful impact on the human genome and health

doi:10.
1016/j.
cell.
2022.
09.
028

Copy number variation (CNV) is a region of the genome that is repeated or deleted in some individuals, and is a common mutation
that makes genes lose function.
The human genome contains hundreds of thousands of CNVs, but typical genomic analysis methods detect only relatively large CNVs, and scientists aren't sure what role most of them do
.

Now, in a new study, researchers from the Broad Institute, Brigham and Women's Hospital and Harvard Medical School have developed a computational method that detected 15 million CNVs in the UK Biodatabase, six times
more than previous analyses of the same data.
Using this method, they discovered hundreds of biological links between these CNVs and dozens of human traits, revealing new links
between specific genes and human traits such as height, blood counts, and health biomarkers.
The results were published in the October 27, 2022 issue of the journal Cell in the paper "Influences of rare copy-number variation on human complex traits.
"

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
09.
028
.

The findings come from the most thorough analysis of the link between CNV and traits to date, and provide a new way to detect and elucidate the effects
of larger structural variations, such as CNV, that affect the genome in complex ways.

Po-Ru Loh, co-corresponding author and assistant professor at Brigham and Women's Hospital, said, "Being able to delve into the potential of these variants gives us more opportunities to discover the ways
in which genetic variants affect human phenotypes.
Downstream, it gives us more clues to explain and understand the complex associations
between genetics and trait variation.
”

9.
Cell: A mystery that has existed for 30 years is finally solved! Uncover the mechanism by which WNK uses phase separation to restore the volume of stressed cells

doi:10.
1016/j.
cell.
2022.
09.
042

In a new study, researchers from the University of Pittsburgh and Carnegie Mellon University took psychedelic films of stressed cells under a microscope, setting them on a journey to solve a mystery: how cells control their own volume
.
Their study explains how scientists used a serendipitous discovery to connect dots in the mystery, first raised 30 years ago
.
The results of the study were published online in the journal Cell on October 31, 2022, in the paper "WNK kinases sense molecular crowding and rescue cell volume via phase separation"
.

Co-first author Daniel Shiwarski, Ph.
D.
, a postdoctoral researcher at Carnegie Mellon University, and his wife, co-first author Cary Boyd-Shiwarski, Ph.
D.
, described how a chance experiment turned into an unexpected discovery, saying, "We were doing in vivo fluorescence imaging experiments unrelated to this study, and when we added a saline solution to the cells, the material inside the cytoplasm quickly turned into a fluorescent lava lamp.
"
。 ”

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
09.
042
.

When cells are suddenly exposed to external stressors, such as high concentrations of salt or sugar, their volume decreases
.
In the early 90s, scientists proposed that a cell somehow regain its volume
by monitoring its protein concentration, or "crowding" within the cell.
But they don't know how the cells feel overcrowded
.
Then, at the beginning of the 21st century, a class of kinases called With-No-Lysine kinase (WNK)
was discovered.
For years, scientists have speculated that WNK reverses cell atrophy, but how they do this is also a mystery
.

The new study addresses both of these puzzles, revealing how WNK kinase activates a "switch" that allows cell volume to be rebalanced
through a process called phase separation.
Dr.
Arohan R.
Subramanya, corresponding author of the paper and associate professor of the Department of Renal Electrolytes at the University of Pittsburgh School of Medicine, said, "Cells contain cytoplasm inside, which is often thought to be diffuse, in which multiple molecules float in a perfectly mixed solution
.
But this remarkable change
occurs in our thinking about how the cytoplasm works.
It's really like an emulsion, containing a bunch of small, tiny protein clusters and droplets that then converge into large droplets when stress like overcrowding occurs, which can be seen
with a microscope.
”

These liquid droplets were the "lava lamps" that Shiwarski and Boyd-Shiwarski saw on that fateful day, when they added a salt solution
to cells in the lab.
They fluorescently labeled WNK1 so that they diffused throughout the cytoplasm, causing the whole cell to glow
.
When this salt solution is added, WNK1 clumps together to form giant neon-green globules that ooze out of the cells like mucus from a lava lamp
.
What they saw was described as phase separation, when WNK1 coagulates into droplets
along with molecules that activate the salt transporter SLC12 in cells.
This step allows the cells to be fed with ions and water at the same time, allowing the volume of the cells to return to their original state
in a matter of seconds.

10.
Cell: Adaptive sequence differences form new neurodevelopment-promoting gene switches in humans

doi:10.
1016/j.
cell.
2022.
10.
016

In a new study, researchers from Duke University in the United States identified a set of human DNA sequences that drive changes in brain development, digestion, and immunity that appear to have evolved rapidly after our lineage split from chimpanzee lineage but before
we split from Neanderthals 。 The findings were published in the November 23, 2022 issue of the journal Cell as "Adaptive sequence divergence forged new neurodevelopmental enhancers in humans.
"

Compared to apes, our brains are larger and our intestines are shorter
.
Craig Lowe, Ph.
D.
, corresponding author and assistant professor of molecular genetics and microbiology at Duke University School of Medicine, said, "In the 7.
5 million years since we separated from our common ancestor from chimpanzees, many traits that we think are unique to humans and unique to humans may have appeared during this period
.
”

Specifically, these are DNA sequence-regulating genes
called Human Ancestor Rapid Evolved Regions (HAQERS).
They are switches
that tell nearby genes when to turn on and off.

Lowe said the rapid evolution of these regions in the genome appears to fine-tune
regulatory control.
As sequences become regulatory regions, more switches are added to the human genome, and they are finely tuned to fit environmental or developmental cues
.
Overall, these changes are beneficial
to our species.
(Biovalley Bioon.
com)