Use Virus Fight Against Bacteria? New Antibacterial Materials Found base on Viruses (Chemistry)

Chinese scientists have recently exploited a new strategy to enhance peptides’ activity against Gram-negative bacteria effectively by conjugating the peptides onto a rod-like virus.  

The work, published online in Nano Letters, was conducted by Prof. NIU Zhongwei and Associate Prof. TIAN Ye from the Technical Institute of Physics and Chemistry (TIPC) of the Chinese Academy of Sciences (CAS).  

Gram-negative bacteria and infection problems caused are threatening global health. Antibiotic resistance is also a serious worldwide problem. Therefore, antimicrobial peptides, which lead to little antibiotic resistance, are regarded as the most promising alternatives to antibiotics. However, compared with the antibiotics, the efficiencies and minimum inhibitory concentration of existing peptides are lower. The clinical applications of peptides are limited.  

In this work, the peptides were “decorated” by conjugating onto one-dimensional rod-like tobacco mosaic virus (TMV). The conjugated peptides could achieve an obvious increased local concentration on the TMV surface. Meanwhile, the interaction area between a rod-like nanoparticle and bacterial cell membrane is becoming larger than the normal area between a spherical nanoparticle and bacterial cell membrane. With the interaction area increased, the destruction to the bacterial cell membrane is stronger.  

As a result, the antibacterial ability of the peptides on the generated peptide-conjugated TMV nanoparticles (peptide-TMV) has extremely enhanced and even achieved hundred times level than free peptides.    

Besides, the conjugated peptides have obtained the ability to inhibit biofilm formation. Through morphology and gene detection of Escherichia coli (E. coli), the damage to E. coli was caused by the destruction of membrane structure, which led to a high osmotic pressure and the generation of reactive oxygen species.  

By experiencing the process, E. coli cell died as the gene expression of biofilm growth was inhibited, and finally biofilm inhibition was achieved. 

This work was supported by the National Key R&D Program, the National Natural Science Foundation of China, the Beijing Natural Science Foundation and the Presidential Foundation of TIPC.  

Featured image: Schematic Illustration of the Peptide-TMV inducing Bacteria‘s Death and Inhibiting Biofilm Formation. (Image by NIU et al.) 


Reference

Conjugating Peptides onto 1D Rodlike Bionanoparticles for Enhanced Activity against Gram-Negative Bacteria


Provided by Chinese Academy of Sciences

Dual-scale Hyperporous Membrane Developed for Efficient “Nonfouling” Oil/Water Separation (Chemistry)

Prof. LIU Fu’s group at the Ningbo Institute of Materials Technology and Engineering (NIMTE) of the Chinese Academy of Sciences (CAS) proposed a poly(vinylidene fluoride) (PVDF) membrane with a dual-scale hyperporous structure and rational wettability, which can achieve a continuous “nonfouling” separation for oil/water emulsions via membrane demulsification, in cooperation with researchers at the University of Hong Kong (HKU). The study was published in ACS Applied Materials & Interfaces

Oily wastewater generated from industrial discharge, ocean oil spills, and human’s daily life has posed great threats to the ecosystem and human health, aggravating the global water shortage.

The membrane separation technique shows its superiority over others on account of its high separation efficiency, cost-effectiveness and ease of operation. However, membrane fouling reduces membrane permeability, thus limiting the practical application of membranes in long-term and efficient oil/water separation.

To achieve a continuous “nonfouling” oil/water emulsion separation, the research group at NIMTE proposesd a dual-scale hyperporous membrane via membrane demulsification. 

The vapor/nonsolvent-induced phase separation (VIPS/NIPS) endowed the PVDF membrane a dual-layer hyperporous structure. Different from common membranes, it consists of primary exterior circular pores (0.5-2.5 μm) and secondary interior pores (0.1-0.3 μm). By virtue of enhanced shearing force, the size-matched primary circular micropores facilitated fluid turbulent motion to achieve breaking up of dispersed oils.  

Through in situ incorporation of hydrophilic poly(hydroxyethyl methylacrylate) (PHEMA), the membranes showed rational surface wettability (contact angle 59 ± 1°), which facilitated the foulant/membrane interaction for “nonfouling” separation. 

The prepared PVDF membrane showed stable permeability (1078 ± 50 Lm-2h-1bar-1) and high separation efficiency (>99.0%) for toluene-in-water emulsion in 2 h of continuous cross-flow filtration without physicochemical washing compared to superwetting membranes. The permeation is composed of two distinct immiscible liquid phases via coalescence demulsification. 

The study has proposed a promising solution to the continuous oil/water separation with negligible fouling via membrane demulsification, and offered insight into the practical application of oil/water separation and fundamental research of membrane demulsification. 

Featured image: The dual-scale hyperporous PVDF Membrane for “nonfouling” oil/water separation (Image by NIMTE)


Reference

Beyond Superwetting Surfaces: Dual-Scale Hyperporous Membrane with Rational Wettability for “Nonfouling” Emulsion Separation via Coalescence Demulsification


Provided by Chinese Academy of Sciences

NASA’s InSight Detects Two Sizable Quakes on Mars (Astronomy)

The magnitude 3.3 and 3.1 temblors originated in a region called Cerberus Fossae, further supporting the idea that this location is seismically active.

NASA’s InSight lander has detected two strong, clear quakes originating in a location of Mars called Cerberus Fossae – the same place where two strong quakes were seen earlier in the mission. The new quakes have magnitudes of 3.3 and 3.1; the previous quakes were magnitude 3.6 and 3.5. InSight has recorded over 500 quakes to date, but because of their clear signals, these are four of the best quake records for probing the interior of the planet.

Studying marsquakes is one way the InSight science team seeks to develop a better understanding of Mars’ mantle and core. The planet doesn’t have tectonic plates like Earth, but it does have volcanically active regions that can cause rumbles. The March 7 and March 18 quakes add weight to the idea that Cerberus Fossae is a center of seismic activity.

“Over the course of the mission, we’ve seen two different types of marsquakes: one that is more ‘Moon-like’ and the other, more ‘Earth-like,’” said Taichi Kawamura of France’s Institut de Physique du Globe de Paris, which helped provide InSight’s seismometer and distributes its data along with the Swiss research university ETH Zurich. Earthquake waves travel more directly through the planet, while those of moonquakes tend to be very scattered; marsquakes fall somewhere in between. “Interestingly,” Kawamura continued, “all four of these larger quakes, which come from Cerberus Fossae, are ‘Earth-like.’”

The new quakes have something else in common with InSight’s previous top seismic events, which occurred almost a full Martian year (two Earth years) ago: They occurred in the Martian northern summer. Scientists had predicted this would again be an ideal time to listen for quakes because winds would become calmer. The seismometer, called the Seismic Experiment for Interior Structure (SEIS), is sensitive enough that, even while it is covered by a dome-shaped shield to block it from wind and keep it from getting too cold, wind still causes enough vibration to obscure some marsquakes. During the past northern winter season, InSight couldn’t detect any quakes at all.

“It’s wonderful to once again observe marsquakes after a long period of recording wind noise,” said John Clinton, a seismologist who leads InSight’s Marsquake Service at ETH Zurich. “One Martian year on, we are now much faster at characterizing seismic activity on the Red Planet.”

Better Detection

The winds may have quieted down, but scientists are still hoping to improve their “listening” capability even more. Temperatures near the InSight lander may swing from almost minus 148 degrees Fahrenheit (minus 100 degrees Celsius) at night to 32 degrees Fahrenheit (0 degrees Celsius) during the day. These extreme temperature variations may be causing the cable connecting the seismometer to the lander to expand and contract, resulting in popping sounds and spikes in the data.

Video: NASA’s InSight lander used a scoop on its robotic arm to begin trickling soil over the cable connecting its seismometer to the spacecraft on March 14, 2021, the 816th Martian day, or sol of the mission. Scientists hope insulating it from the wind will make it easier to detect Mars quakes. Credits: NASA/JPL-Caltech

So the mission team has begun trying to partially insulate the cable from the weather. They’ve started by using the scoop on the end of InSight’s robotic arm to drop soil on top of the domed Wind and Thermal Shield, allowing it to trickle down onto the cable. That allows the soil to get as close to the shield as possible without interfering with the shield’s seal with the ground. Burying the seismic tether is in fact one of the goals of the next phase of the mission, which NASA recently extended by two years, to December 2022.

Despite the winds that have been shaking the seismometer, InSight’s solar panels remain covered with dust, and power is running lower as Mars moves away from the Sun. Energy levels are expected to improve after July, when the planet begins to approach the Sun again. Until then, the mission will successively turn off the lander’s instruments so that InSight can hibernate, waking periodically to check its health and communicate with Earth. The team hopes to keep the seismometer on for another month or two before it has to be temporarily turned off.

More About the Mission

JPL manages InSight for NASA’s Science Mission Directorate. InSight is part of NASA’s Discovery Program, managed by the agency’s Marshall Space Flight Center in Huntsville, Alabama. Lockheed Martin Space in Denver built the InSight spacecraft, including its cruise stage and lander, and supports spacecraft operations for the mission.

A number of European partners, including France’s Centre National d’Études Spatiales (CNES) and the German Aerospace Center (DLR), are supporting the InSight mission. CNES provided the Seismic Experiment for Interior Structure (SEIS) instrument to NASA, with the principal investigator at IPGP (Institut de Physique du Globe de Paris). Significant contributions for SEIS came from IPGP; the Max Planck Institute for Solar System Research (MPS) in Germany; the Swiss Federal Institute of Technology (ETH Zurich) in Switzerland; Imperial College London and Oxford University in the United Kingdom; and JPL. InSight’s Marsquake Service is a collaborative ground service operation led by ETH Zurich that also includes on-duty seismologists from IPG Paris, University of Bristol and Imperial College London. SEIS and APSS Operations are led by CNES SISMOC, with support of CAB, and SEIS data are formatted and distributed by the IPG Paris Mars SEIS Data Service. DLR provided the Heat Flow and Physical Properties Package (HP3) instrument, with significant contributions from the Space Research Center (CBK) of the Polish Academy of Sciences and Astronika in Poland. Spain’s Centro de Astrobiología (CAB) supplied the temperature and wind sensors.

Featured image: This artist’s concept shows the InSight lander, its sensors, cameras and instruments. Credit: NASA/JPL-Caltech


Provided by NASA

Realtime Imaging of Female Gamete Formation in Plants (Botany)

New research from Japanese scientists offers a glimpse of how female gametes’ cell fates are determined and shows promise for future progress in plant breeding

Scientists from Nagoya University, Yokohama City University and Chubu University have developed a system which enables the live imaging of the formation of the female gamete in plants.

In flowering plants, the sperm cell and egg cell meet and fertilization takes place in the flower. While sperm cells are made in the pollen, egg cells are made in the ovule, the structure that becomes the seed. However, as the ovule is buried deep within the pistil, it has thus far been impossible to observe the formation of the egg cell in living plants.

The team, led by Dr Daisuke Kurihara and Dr Tetsuya Higashiyama of Nagoya University Institute of Transformative Bio-Molecules (WPI-ITbM), Dr Daichi Susaki of Yokohama City University Kihara Institute for Biological Research and Dr Takamasa Suzuki of Chubu University College of Bioscience and Biotechnology, using the ovule culturing technology that they had developed previously, succeeded in capturing images of the egg cell being formed inside the ovule. On top of that, they were able to isolate the egg cell and its neighboring cells, and by analyzing the genes expressed in these few cells, identify how the cells adjoining the egg cell determine its fate.

Living things which carry out sexual reproduction produce offspring via a fertilization process involving male and female gametes. In animals, the female gamete (the egg) is produced by meiosis, a type of cell division that halves the number of chromosomes present in the cell. However, the process in flowering plants is rather more lengthy. Following meiosis, karyomitosis (nuclear division) takes place three times within the cell, resulting in the production of a single cell with eight nuclei. This cell then divides, producing cells with a variety of different roles including two gametes, the egg cell and central cell, and the synergid cells. However, it was not yet understood precisely how the two female gametes were produced among the seven new cells that result from this process of division.

Using an ovule culturing method that they had developed previously, the research team attempted the observation in real time of the formation of the female gamete in Arabidopsis thaliana. They saw that when the first nuclear division takes place, the resulting two nuclei go to the opposite ends of the cell. Dividing again into four, the nuclei then line up along the edge of the cell. Finally, dividing again into eight, the plasma membranes are constructed around the nuclei, forming the cells which are attached to the two gametes (the egg cell and central cell). Having observed 157 cases of this division, they found that the nuclei close to where the pollen tube penetrates would become the nuclei of the synergid, egg and central cells, demonstrating that the position of the nuclei within the cell has a strong correlation with cell fate.

Continuing, in order to find out when the various cells’ fates are determined, they analyzed the time at which expression of the specific transcription factor myb98, important for the differentiation and function of the synergid cells, commenced. They found that myb98 begins to be expressed very shortly after the nuclei divide into 8 and are enclosed by the plasma membranes. Given that the specific transcription factor for the egg cell can also be found in the egg cell at the same early stage, it can be considered that cell fate is determined immediately after the formation of the plasma membranes, or possibly even earlier.

The time at which cell fate is determined is significant because it gives us an insight into how plants remain adaptable to environmental conditions by flexibly changing cell fate and thus ensuring the survival of crucial cells such as gametes.

Looking to the future, the research team’s focus will be on discovering how the cell fate change is accomplished, and explaining its molecular mechanism. Once the molecular mechanism has been analyzed, it is expected that this field of research will contribute to the development of methods to increase plant fertilization rates and environmental resistance, offering the prospect of solving key issues in food supply that affect millions of people around the world.

Featured image: Development of the female gamete was observed over 20 hours, clearly showing the division of the nuclei and formation of the egg, central and synergid cells. © Issey Takahashi


Reference: Susaki D, Suzuki T, Maruyama D, Ueda M, Higashiyama T, Kurihara D (2021) Dynamics of the cell fate specifications during female gametophyte development in Arabidopsis. PLoS Biol 19(3): e3001123. doi: 10.1371/journal.pbio.3001123


Provided by Nagoya University

Protein Based Biomarker Identifies the Chemo Drug Sensitivity (Medicine)

Cancer is the world’s second deadliest disease which contributes towards the fatality of over 10 million people per year. Oncologists adopt a variety of treatment procedures to treat cancer cells. Among the different methods used to fight cancer, chemotherapeutic treatment is a prominent and well-adopted technique. It is a drug based method, wherein powerful chemical compounds are injected into the body to annihilate the malignant cells. Although these chemicals support the destruction of the cancerous cells, optimizing their dosage has always been a challenge to the medical specialists.

Cisplatin is a chemotherapy medication which is used to treat a number of cancers such as lung cancer, brain tumor, breast cancer, liver cancer etc. This platinum-metal based chemotherapy drug is highly powerful and is instituted by the intravenous route into the body. Although it is renowned for effective destruction of cancerous cells for the past 4 decades, its alarming side effects is of serious concern to the medical community. Researchers have reported that administration of high dosage of the chemical is not only ineffective on the tumor cells but is also responsible for adverse side effects which may even lead to the sudden demise of the patient. control on the level of the cisplatin drug has been a matter of persisting concern for medical practitioners.  A recent study on monitoring the cisplatin level in liver cancer cells reported by researchers from the Graduate School of Medical and Dental Sciences at Niigata University and their collaborators from Niigata Medical Center, Uonuma Institute of Community Medicine Niigata University Hospital, Niigata City General Hospital, Saiseikai Niigata Hospital and, Kashiwazaki General Hospital and Medical Center provides a ray of hope to the health professionals. The findings were published recently in the prestigious Scientific Reports journal from Nature publishing house. The multi-disciplinary research team has identified adipose most abundant 2 protein (APM2) as a potential marker to indicate the permissible level of the drug. They have experimentally investigated the liver and gastro cancer cells and have compared the variation in the protein concentration in the presence and absence of the chemo drug.

Over expression of APM2 induce resistance to cisplatin © Nigata University

“Our results demonstrate a significant relationship between the high level of APM2 expression in serum, cancerous cells in the liver, the surrounding liver tissue and cisplatin resistance. The study reveals that APM2 expression is related to cisplatin sensitivity” explains Professor Kenya Kamimura of the Division of Gastroenterology and Hepatology, the Graduate School of Medical and Dental Sciences, Niigata University. The research study paves way for effective monitoring of chemotherapeutic drug level and their safe administration. Professor Kenya Kamimura states with confidence that, “The serum APM2 can be an effective biomarker of the liver and gastric cancer cells for determining the sensitivity to cisplatin.  The results of the study would provide an advantage for the technicians, allowing easy adaption in small local clinics.”

The research group has noticed that APM2 concentration favours the development of ERCC6L gene card. This is manifested by the growth of the cancerous cells and marks the resistance to the chemo drug.  The valuable findings offers the potential to control the cisplatin dosage level and avoid cytotoxicity. Such a study is essential in today’s context as research groups across the globe strive to develop new methodologies to optimize the dosage and control the severe side-effects induced by the concentration of chemo drugs. The research team has also utilized bioinformatics based tools to complement the experimentally obtained results.

Serum APM2 concentration could estimate the cisplatin sensitivity of the liver cancer © Nigata University

“To the best of our knowledge, this is the first report to demonstrate that the serum level of APM2 can be the predictor of the CDDP chemosensitivity. This study thus represents a milestone for detecting CDDP sensitivity, and further studies will help modify APM2 expression, which could contribute to the chemosensitization of the tumor” describes Professor Kenya Kamimura.

The interesting results of the research study has laid a foundation to track the chemo drug level. Future studies will explore the mechanism and relation between APM2 and ERCC6L. Such studies are on the cutting edge research areas of oncological sciences and hold immense potential in further extending the results to other types of cancers.

The research in the authors’ laboratories has been supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Sciences 20390205, 25670370, and 23659395 to Takeshi Suda and Yutaka Aoyagi; 17K09408 to Kenya Kamimura; and grant provided from the Ichiro Kanehara Foundation.

Featured image: APM2 overexpression increases ERCC6L expression © Nigata University


Publication Details

Journal: Scientific Reports
Title: Adipose Most Abundant 2 Protein is a Predictive Marker for Cisplatin Sensitivity in Cancers
Authors: Kenya Kamimura, Takeshi Suda, Yasuo Fukuhara, Shujiro Okuda, Yu Watanabe, Takeshi Yokoo, Akihiko Osaki, Nobuo Waguri, Toru Ishikawa, Toshihiro Sato, Yutaka Aoyagi, Masaaki Takamura, Toshifumi Wakai & Shuji Terai
DOI: 10.1038/s41598-021-85498-7


Provided by Nigata University

The First Non-invasive Biomarker to Track and Verify Efficacy of Senolytic Drugs (Medicine)

The discovery and development of a lipid-metabolite biomarker is expected to facilitate research and clinical trials of drugs that target multiple age-related diseases

Buck Institute researchers have discovered and are developing a novel, non-invasive biomarker test that can be used to measure and track performance of senolytics: a class of drugs that selectively eliminate senescent cells. The discovery is expected to play a major role in efforts to develop treatments that would battle a myriad of chronic age-related conditions that range from arthritis to lung disease to Alzheimer’s disease and glaucoma. This biomarker is a unique signaling lipid metabolite, normally exclusively intracellular, but is released when senescent cells are forced to die. This metabolite is detectible in blood and urine, making non-invasive testing possible. With a growing list of senolytic drugs in development, detecting this metabolite via a companion test could verify performance of senolytic candidates.

“The list of age-related diseases definitively linked to cellular senescence keeps growing, as does the number of biotech companies racing to develop drugs to eliminate senescent cells,” said Buck professor Judith Campisi, PhD, senior scientist on the study. “While the field has never been more promising, the lack of a simple biomarker to measure and track efficacy of these treatments has been a hindrance to progress. We are excited to bring this new biomarker to the field and look forward to it being used in the clinic.”

Understanding senescence and identifying lipids as a new and potent component of the SASP

During cellular senescence, stressed or damaged cells permanently stop dividing, a putative mechanism to safeguard against cancer. Senescent cells are not dead – they spew out a stew of bioactive molecules that promote wound healing and chronic inflammation, the latter playing a major role in many age-related diseases as the cells accumulate over time. This bioactive stew is known as the SASP (senescence-associated secretory phenotype); its composition, and deleterious effects have been well-studied.

This work, performed in human cell culture and mice, shows that senescent cells also synthesize a large array of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. “Lipid components of the SASP have been vastly understudied,” says lead scientist Christopher Wiley, PhD, a former assistant research professor at the Buck, now at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston. “The biosynthesis of these signaling lipids promotes segments of the SASP and reinforces the permanent growth arrest of senescent cells. This work provides a new way of understanding and studying senescence-driven pathology,” he said. Oxylipins are implicated in many inflammatory conditions including cardiovascular disease and pain response. Many commonly used drugs, such as aspirin and ibuprofen, act by preventing oxylipin synthesis.

The biomarker is exclusive to senescent cells and may be of interest in cancer research

Wiley says senescent cells change their fatty acid metabolism and they do it in such a way that free polyunsaturated fatty acids accumulate inside the arrested cells where they are used to manufacture oxylipins. Researchers identified one of these fatty acids, 15-deoxy-delta-12, 14-prostaglandin J2 (dihomo-15d-PGJ2), as unique to senescent cells; it accumulates inside senescent cells and is released when the cells die. In this study, mice were given chemotherapy which induces widespread senescence, followed by a senolytic drug. The biomarker was only detected in the blood and urine of mice treated with both chemotherapy and the senolytic, but not with either on its own, confirming specificity for senolysis.

Researchers also showed that dihomo-15d-PGJ2 had a functional role in senescence. Inhibiting its synthesis allowed a subset of cells to escape senescence and continue dividing, and had a less inflammatory SASP profile. Addition of dihomo-15d-PGJ2 to non-senescent cell drove them into senescence by activating RAS, a cancer-promoting gene that is also known to cause senescence.

“We hope that identifying and including these bioactive lipids as part of the SASP will encourage researchers working in a broad range of fields to take a new look at cellular senescence,” said Campisi. “The fact that one of these lipids ends up being a simple non-invasive biomarker for tracking the efficacy of treatments is a huge plus for those of us working to stem the ravages of age-related disease.”

Featured image: Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis © Christopher Wiley, PhD

Reference: Christopher D. Wiley, Rishi Sharma, Sonnet S. Davis, Jose Alberto Lopez-Dominguez, Kylie P. Mitchell, Samantha Wiley, Fatouma Alimirah, Dong Eun Kim, Therese Payne, Andrew Rosko, Eliezer Aimontche, Sharvari M. Deshpande, Francesco Neri, Chisaka Kuehnemann, Marco Demaria, Arvind Ramanathan, Judith Campisi, Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis, Cell Metabolism, 2021, , ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2021.03.008. (https://www.sciencedirect.com/science/article/pii/S1550413121001157)


Provided by Buck Institute for Research on Aging

Therapeutic Resistance Linked to Softer Tissue Environment in Breast Cancer (Medicine)

Researchers at the University of California, San Francisco, have discovered that aggressive, triple-negative breast cancers (TNBCs) can evade treatment by reorganizing and softening the collagen matrix that surrounds the cancer cells. The study, which will be published April 2 in the Journal of Experimental Medicine (JEM), shows that the softer matrix activates a signaling pathway that promotes the cancer cells’ survival, and suggests that targeting this pathway could enhance the effectiveness of chemo- and radiotherapy in TNBC patients.

TNBC is an aggressive type of breast cancer with worse survival rates than other forms of the disease. Because TNBC cells lack the HER2 signaling receptor and the estrogen and progesterone hormone receptors, they cannot be eliminated by drugs that specifically target these proteins. Instead, TNBC patients are normally treated with a combination of surgery and chemotherapy/radiation, but these treatments are often unable to completely eliminate the tumor, leading to local recurrence and metastasis to other tissues.

“Currently, there are no reliable methods to identify patients that are likely to respond well and those that are likely to be resistant to treatment,” says Valerie M. Weaver, a professor and Director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery at UCSF. “There is an urgent need for a deeper understanding of the biological basis for therapeutic response in TNBC that will inform treatment decisions and the development of effective strategies to overcome therapy resistance.”

Compared with an untreated breast tumor (left), NF-κB (brown) is elevated in a residual tumor after therapy (right) due to a softening of the extracellular matrix. NF-κB promotes the cancer cells’ survival and subsequent tumor relapse. ©2021 Drain et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20191360

One factor that could influence the response to therapy is the meshwork of collagen and other proteins that surrounds the cancer cells within tumors. This extracellular matrix can activate various signaling pathways within cells that determine whether or not cells die when they are exposed to stress.

Weaver and colleagues, including Catherine C. Park, professor and Chair of the Department of Radiation Oncology at UCSF, and graduate student Allison P. Drain, analyzed the extracellular matrix in tumor samples taken from TNBC patients. In untreated TNBC, collagen proteins were aligned into long, linear fibers, creating a matrix that is much stiffer than normal, healthy breast tissue. But in TNBC treated with chemotherapy, the collagen fibers in the remaining tumor were reorganized to form a much softer matrix.

“This raised the intriguing possibility that the softened, remodeled extracellular matrix might be causally linked to the pathogenesis of the treatment-resistant, residual tumor tissue,” Weaver says.

The researchers found that tumors grown in the lab or in mice were more resistant to both radiation and the chemotherapy agent paclitaxel when they were surrounded by a softer extracellular matrix. Cancer cells grown in a stiff environment activate a signaling protein called JNK that makes the cells more likely to die in response to stress. In contrast, cancer cells surrounded by a softer matrix activate a protein called NF-kB that counteracts JNK and promotes cell survival. Accordingly, treating mice with a drug that inhibits NF-kB improved their therapeutic response, significantly slowing tumor growth when combined with radiotherapy.

Weaver and colleagues found that TNBC patients whose tumors had high levels of NF-kB activity showed higher rates of treatment resistance. NF-kB activity was also elevated in remodeled, softened tumors that remained after treatment.

“Therapies designed to modulate stiffness-dependent NF-κB or JNK activity might therefore improve the treatment response of TNBCs and enhance the long-term survival of these patients,” Weaver says. “However, further efforts will be needed to clarify the nature of the mechanisms that mediate treatment resistance and develop effective, selective, and safe therapeutics.”

Featured image: Compared with an untreated breast tumor (left), the extracellular collagen matrix (blue) is reorganized in a residual tumor after therapy (right), activating a signaling pathway in tumor cells (magenta) that allows them to survive and initiate tumor recurrence. ©2021 Drain et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20191360


Reference: Drain et al. 2021. J. Exp. Med.
https://rupress.org/jem/article-lookup/doi/10.1084/jem.2019360?PR

Provided by Rupress

Targeting MicroRNAs Could Unmask Hidden Vulnerability in Breast Cancer Stem Cells (Medicine)

Researchers in Italy have identified a pair of microRNA molecules that help maintain a population of cancerous stem cells that drive the growth of breast cancers and initiate tumor relapse after treatment. The study, which will be published April 2 in the Journal of Cell Biology (JCB), reveals that targeting these microRNAs makes cancer stem cells more susceptible to some chemotherapies and could potentially improve the prognosis of patients with aggressive forms of breast cancer.

Many tumors contain a small population of cancer stem cells that initiate tumor growth and give rise to the various cell types found in tumors. Moreover, because cancer stem cells are often resistant to radio- and chemotherapies, they can survive and promote tumor relapse and metastasis after initial rounds of treatment. In breast cancer, for example, tumors containing a relatively high number of cancer stem cells have a much poorer prognosis than tumors with fewer stem cells.

Eliminating these stem cells may therefore be crucial for the successful treatment of breast cancer and other tumor types. One class of molecule that might help cancer stem cells to persist within tumors is microRNAs. These short RNA molecules control the fate and identity of cells by regulating the levels of hundreds of longer, protein-encoding “messenger” RNAs.

“We wanted to identify microRNAs required for the maintenance of normal mammary stem cells that are inherited by cancer stem cells and could represent potential therapeutic targets in breast cancer,” says Francesco Nicassio, a principal investigator and Center Coordinator of the Center for Genomic Science at the Italian Institute of Technology in Milan.

In the new study, Nicassio and colleagues, including co-senior author Pier Paolo Di Fiore, a group leader at the European Institute of Oncology and professor at the University of Milan, identified two closely related microRNAs, miR-146a and miR-146b, that are present in breast cancer stem cells as well as normal mammary stem cells. Indeed, the levels of these two microRNAs tended to be highly elevated in aggressive breast cancers that have a high number of cancer stem cells and a poor prognosis.

The researchers found that miR-146a/b are required to maintain the pool of cancer stem cells. Depleting these two microRNAs from patient-derived cancer cells reduced the ability of these cells to form new tumors when implanted into mice.

Nicassio and colleagues determined that miR-146a/b regulate hundreds of messenger RNAs, thereby controlling numerous cellular processes such as metabolism and DNA replication. Depleting miR-146a/b from cancer stem cells might alter these processes in ways that leave the cells more vulnerable to chemotherapy. Nicassio and colleagues found that reducing the levels of miR-146a/b made breast cancer stem cells over 20 times more sensitive to methotrexate, significantly improving this metabolic inhibitor’s ability to restrict tumor growth in mice.

“While the molecular details remain to be determined, our results clearly show that reducing miR-146a/b levels represents an attractive approach to overcome some forms of drug resistance in the clinical setting, unmasking a ‘hidden vulnerability’ exploitable for the development of anti-cancer stem cell therapies,” Nicassio says.

Featured image: Tumor sample from a breast cancer patient expressing high levels of the microRNAs miR-146a and miR-146b. ©2021 Tordonato et al. Originally published in Journal of Cell Biology. https://doi.org/10.1083/jcb.202009053


Reference: Tordonato et al., “miR-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer”, 2021. J. Cell Biol.
https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.202009053?PR


Provided by Rockefeller University Press

Oxygen-promoted Synthesis Of Armchair Graphene Nanoribbons on Cu(111) (Material Science)

On-surface synthesis has received great attention as a method to create atomically-precise one-dimensional (1D) and two-dimensional (2D) polymers with intriguing properties. In particular, graphene nanoribbons (GNRs), a category of quasi-1D nanomaterials derived from graphene, have been widely studied due to their tunable electronic properties and potential applications in semiconductor devices, such as field-effect transistors and spintronics. A series of top-down approaches have been pursued to produce GNRs, but a lack of control over the ribbon width and edge structure has hindered their further development.

In 2010, Cai et al. firstly reported the fabrication of an atomically-precise armchair GNR (AGNR) on the Au(111) surface using a bottom-up approach. The basic mechanism involves thermally-activated dehalogenation, surface-assisted polymerization and finally cyclodehydrogenation.

In the following decade, this bottom-up approach has been extended to synthesize a wide variety of GNRs, including AGNRs with different widths, zigzag GNRs, GNR heterojunctions, chiral GNRs and chemically- doped GNRs. Based on the periodic similarity of their electronic structures, AGNRs can be classified into three families, 3p, 3p+1 and 3p+2 (representing the number of carbon atoms in the narrow direction).

So far, few studies have focused on GNR synthesis on Cu(111) due to the stronger surface interaction, despite the lower temperature for dehalogenation. It has been shown that chiral GNRs can be synthesized on Cu(111) using the same precursor which yields non-chiral 7-AGNR on Au(111) and that dehalogenation can be reversible on Au(111) but not Cu(111), which implies that the reaction pathway and products achieved could be controlled through the choice of substrate.

A second approach to tailor the reaction pathway in surface-confined synthesis is to introduce different atomic species, which has been considered in only a few recent studies. Exposure to iodine creates a monolayer intercalated between the polymers and the Ag(111) surface that decouples their electronic interactions. In addition, hydrogen was shown to remove halogen by-products and to induce covalent coupling, and sulphur to switch the surface-confined Ullmann reaction on or off.

Prof. Lifeng Chi’s research group in Soochow University recently investigated the effect of oxygen on the synthesis of 3-AGNRs by surface-confined Ullmann coupling and determined that it, instead, caused a 1D to 2D transformation of the organometallic (OM) structures.

Here, their objective was to investigate the synthesis of 3p-AGNRs on Cu(111), extending from the previous study on Au(111), and to examine the effect of oxygen on lateral fusion of 3-AGNRs, inspired by their potential to promote C-H activation.

Their investigation demonstrated the successful synthesis of 3p-AGNRs on Cu(111) via lateral fusion of poly(para-phenylene) (i.e. 3-AGNR). Introduction of co-adsorbed atomic oxygen substantially reduced the temperature required to induce the lateral fusion reaction. The identification of this catalytic effect could benefit on-surface synthesis that applies dehydrogenation reactions, not restricting to GNRs, and highlights the potential of additional atomic adsorbates to steer surface reactions.


See the article: Ji P, Maclean O, Galeotti G, Dettmann D, Berti G, Sun K, Zhang H, Rosei F, Chi L. Oxygen-promoted synthesis of armchair graphene nanoribbons on Cu(111). Sci China Chem, 2021, 64, https://doi.org/10.1007/s11426-021-9966-x https://link.springer.com/article/10.1007/s11426-021-9966-x


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