The Tuberculosis Pathogen Releases its Toxin by a Novel Protein Transport System (Medicine)

This transport system may be widespread across many Gram-positive bacteria that contain proteins in the WXG100 superfamily. Tuberculosis kills 1 million people each year.

Six years ago, Michael Niederweis, Ph.D., described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis. This toxin, tuberculosis necrotizing toxin, or TNT, became the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. The toxin is released as M. tuberculosis bacteria survive and grow inside their human macrophage host, killing the macrophage and allowing the escape and spread of the bacteria.

For 132 years, the lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death. M. tuberculosis infects 9 million people a year and kills more than 1 million.

Now, in another groundbreaking work, the University of Alabama at Birmingham researcher and colleagues describe how two small ESX proteins made by the M. tuberculosis bacteria mediate secretion of TNT by pore formation in the membranes that envelop the bacteria. This finding may have broad application because a distinctive three-amino acid motif found on EsxE and EsxF — tryptophan/any-amino-acid/glycine, known in shorthand as WXG — is also found on many other small mycobacterium proteins and on the large WXG100 superfamily of bacterial proteins that resemble EsxE and EsxF.

“Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion,” said Niederweis, a professor in the UAB Department of Microbiology. “Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria.”

TNT is one of two domains in the M. tuberculosis outer membrane protein CpnT; activity of the TNT domain of CpnT in the cytosol of the macrophage induces macrophage death by hydrolyzing NAD+. M. tuberculosis has an inner membrane and an outer membrane, and a protein needs to get through each layer to be secreted outside of the bacterium. How CpnT gets to the outer membrane was unknown.

EsxE and EsxF are part of the same gene segment as CpnT, and the UAB researchers hypothesized that the two small proteins might be involved in secretion of the toxin.

By creating different strains that lacked either EsxE or EsxF, they showed that both proteins were necessary for the translocation of CpnT to the cell surface of M. tuberculosis and for the secretion of TNT into the cytosol of macrophages infected with M. tuberculosis. Furthermore, EsxE and EsxF are surface-accessible proteins on M. tuberculosis as a membrane-associated complex.

To learn more about the mechanism of that translocation, the UAB team made mutants of each Esx protein, where the tryptophan amino acid of the single WXG motif on each protein was replaced by the amino acid alanine. The mutants showed that an intact WXG motif on EsxE and on EsxF were required for efficient CpnT translocation to the outer membrane of M. tuberculosis and subsequent TNT secretion into the cytosol of infected macrophages.

Purification of the water-soluble EsxE and EsxF proteins showed they formed EsxE-EsxF dimers, and five of these dimers assembled into star-shaped structures, as viewed by electron microscopy. Each was about 10 nanometers across, with a 3-nanometer central pore.

Experiments with planar lipid bilayers were key to understanding the molecular function of EsxE-EsxF, as they showed that the EsxE-EsxF pores formed channels through lipid membranes.

Finally, the researchers showed that the WXG motifs were required for pore formation and membrane disruption by the EsxE-EsxF complex, and the motifs mediated assembly of functional EsxE-EsxF oligomers. This now defines a biochemical role for the previously enigmatic WXG motif.

“EsxE and EsxF constitute the first known outer membrane components mediating protein secretion in M. tuberculosis,” Niederweis said. “However, it is unlikely that EsxE and EsxF are sufficient for TNT secretion, since an energy source is required in all known bacterial protein secretion systems. Therefore, it is possible that EsxE-EsxF associate with other proteins or protein complexes to achieve CpnT export and TNT secretion.”

The UAB researchers propose two models for the transport of CpnT by EsxE and EsxF. In the first, the EsxE-EsxF heterodimers form a pore in the inner membrane, and then form another pore in the outer membrane to create transmembrane channels. “Alternatively,” Niederweis said, “the inner membrane channel is extended to span the periplasm via filament formation, and connects to EsxE-EsxF pores in the outer membrane, exposing EsxF on the cell surface. In this model, the putative EsxE-EsxF channel tunnel enables export of the CpnT polypeptide to the outer membrane of M. tuberculosis, and subsequent secretion of TNT and EsxE-EsxF.”

Co-authors with Niederweis in the study, “Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis,” published in Nature Communications, are Uday Tak and Terje Dokland, UAB Department of Microbiology.

“This work was a remarkable achievement of an outstanding graduate student, Uday Tak, who did almost all of these experiments by himself,” Niederweis said. Uday Tak obtained his Ph.D. in November 2020 and is now a postdoctoral fellow at the University of Colorado-Boulder.

This paper was selected by the editor-in-chief as a highlight and is featured on a special website called “Microbiology and infectious diseases.”

Support came from National Institutes of Health grant AI121354. Electron microscopy data analysis was performed on the UAB CHEAHA supercomputer platform, which is supported by National Science Foundation grant OAC-1541310.

At UAB, Niederweis holds the Endowed Professorship in Bacteriology.

Featured image: Michael Niederweis © UAB


Reference: Tak, U., Dokland, T. & Niederweis, M. Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis. Nat Commun 12, 394 (2021). https://www.nature.com/articles/s41467-020-20533-1 https://doi.org/10.1038/s41467-020-20533-1


Provided by University of Alabama at Birmingham

Researchers Validate New Technique for Rapidly Diagnosing Herbicide-resistant Weeds (Agriculture)

A recent article in the journal Weed Science describes a new rapid ‘leaf-disk assay’ that uses chlorophyll fluorescence emissions to determine whether a weed is resistant to various systemic and contact herbicides

As the number of weed populations resistant to multiple herbicides continues to soar, it is clear that better tools are needed to help growers rapidly diagnose resistance issues. With more timely access to information, they can take earlier, proactive steps to keep resistant weeds from spreading.

A recent article in the journal Weed Science describes a new rapid “leaf-disk assay” that uses chlorophyll fluorescence emissions to determine whether a weed is resistant to various systemic and contact herbicides. In contrast to time-consuming and labor-intensive greenhouse screenings and population studies, leaf-disk assay results are available in about 48 hours.

In a recent research study, scientists were able to use the fluorescence technique to rapidly detect resistance to glyphosate, dicamba and fomesafen in broadleaf and grass weeds, including Palmer amaranth, waterhemp, kochia and goosegrass.

The assay clearly separated populations susceptible to herbicides from those that are highly resistant. It exhibited less sensitivity, though, in identifying populations with lower levels of resistance.

Though further work is needed to fine-tune the new test for greater precision, researchers say it holds great promise.

“In addition to the speed, the leaf-disk assay requires fewer technical skills,” says Chenxi Wu, research scientist at Bayer CropScience. “That means more weed science labs will be able to use the technique to identify multiple resistances efficiently – helping growers take more immediate and informed actions.”

To learn more, read the article “A nondestructive leaf-disk assay for rapid diagnosis of weed resistance to multiple herbicides” online.


Reference: Wu, C., Varanasi, V., & Perez-Jones, A. (2021). A nondestructive leaf-disk assay for rapid diagnosis of weed resistance to multiple herbicides. Weed Science, 1-10. doi:10.1017/wsc.2021.15


Provided by Cambridge University Press

NASA’s NICER Finds X-ray Boosts in the Crab Pulsar’s Radio Bursts (Astronomy)

A global science collaboration using data from NASA’s Neutron star Interior Composition Explorer (NICER) telescope on the International Space Station has discovered X-ray surges accompanying radio bursts from the pulsar in the Crab Nebula. The finding shows that these bursts, called giant radio pulses, release far more energy than previously suspected.

Video: Observations from NASA’s Neutron star Interior Composition Explorer (NICER) show X-ray boosts linked in the Crab pulsar’s random giant radio pulses. Watch to learn more.Credit: NASA’s Goddard Space Flight Center

A pulsar is a type of rapidly spinning neutron star, the crushed, city-sized core of a star that exploded as a supernova. A young, isolated neutron star can spin dozens of times each second, and its whirling magnetic field powers beams of radio waves, visible light, X-rays, and gamma rays. If these beams sweep past Earth, astronomers observe clock-like pulses of emission and classify the object as a pulsar.

“Out of more than 2,800 pulsars cataloged, the Crab pulsar is one of only a few that emit giant radio pulses, which occur sporadically and can be hundreds to thousands of times brighter than the regular pulses,” said lead scientist Teruaki Enoto at the RIKEN Cluster for Pioneering Research in Wako, Saitama prefecture, Japan. “After decades of observations, only the Crab has been shown to enhance its giant radio pulses with emission from other parts of the spectrum.”

The new study, which will appear in the April 9 edition of Science and is now available online, analyzed the largest amount of simultaneous X-ray and radio data ever collected from a pulsar. It extends the observed energy range associated with this enhancement phenomenon by thousands of times.

Located about 6,500 light-years away in the constellation Taurus, the Crab Nebula and its pulsar formed in a supernova whose light reached Earth in July 1054. The neutron star spins 30 times each second, and at X-ray and radio wavelengths it is among the brightest pulsars in the sky.

Between August 2017 and August 2019, Enoto and his colleagues used NICER to repeatedly observe the Crab pulsar in X-rays with energies up to 10,000 electron volts, or thousands of times that of visible light. While NICER was watching, the team also studied the object using at least one of two ground-based radio telescopes in Japan – the 34-meter dish at the Kashima Space Technology Center and the 64-meter dish at the Japan Aerospace Exploration Agency’s Usuda Deep Space Center, both operating at a frequency of 2 gigahertz.

Between 2017 and 2019, NASA’s Neutron star Interior Composition Explorer (NICER) and radio telescopes in Japan studied the Crab pulsar at the same time. In this visualization, which represents just 13 minutes of NICER observations, millions of X-rays are plotted relative to the pulsar’s rotational phase, which is centered on the strongest radio emission. For clarity, two full rotations are shown. As the pulsar beams sweep across our line of sight, they produce two peaks for each rotation, with the brighter one associated with greater numbers of giant radio pulses. For the first time, NICER data show a slight increase in X-ray emission associated with these events. Credits: NASA’s Goddard Space Flight Center/Enoto et al. 2021

The combined dataset effectively gave the researchers nearly a day and a half of simultaneous X-ray and radio coverage. All told, they captured activity across 3.7 million pulsar rotations and netted some 26,000 giant radio pulses.

Giant pulses erupt quickly, spiking in millionths of a second, and occur unpredictably. However, when they occur, they coincide with the regular clockwork pulsations.

NICER records the arrival time of every X-ray it detects to within 100 nanoseconds, but the telescope’s timing precision isn’t its only advantage for this study.

“NICER’s capacity for observing bright X-ray sources is nearly four times greater than the combined brightness of both the pulsar and its nebula,” said Zaven Arzoumanian, the project’s science lead at NASA’s Goddard Space Flight Center in Greenbelt, Maryland. “So these observations were largely unaffected by pileup – where a detector counts two or more X-rays as a single event – and other issues that have complicated earlier analyses.”

Enoto‘s team combined all of the X-ray data that coincided with giant radio pulses, revealing an X-ray boost of about 4% that occurred in synch with them. It’s remarkably similar to the 3% rise in visible light also associated with the phenomenon, discovered in 2003. Compared to the brightness difference between the Crab’s regular and giant pulses, these changes are remarkably small and provide a challenge for theoretical models to explain.

The enhancements suggest that giant pulses are a manifestation of underlying processes that produce emission spanning the electromagnetic spectrum, from radio to X-rays. And because X-rays pack millions of times the punch of radio waves, even a modest increase represents a large energy contribution. The researchers conclude that the total emitted energy associated with a giant pulse is dozens to hundreds of times higher than previously estimated from the radio and optical data alone.

“We still don’t understand how or where pulsars produce their complex and wide-ranging emission, and it’s gratifying to have contributed another piece to the multiwavelength puzzle of these fascinating objects,” Enoto said.

NICER is an Astrophysics Mission of Opportunity within NASA’s Explorers program, which provides frequent flight opportunities for world-class scientific investigations from space utilizing innovative, streamlined and efficient management approaches within the heliophysics and astrophysics science areas. NASA’s Space Technology Mission Directorate supports the SEXTANT component of the mission, demonstrating pulsar-based spacecraft navigation.

Banner: The Crab Nebula, the six-light-year-wide expanding cloud of debris from a supernova explosion, hosts a neutron star spinning 30 times a second that is among the brightest pulsars in the sky at X-ray and radio wavelengths. This composite of Hubble Space Telescope images reveals different gases expelled in the explosion: blue reveals neutral oxygen, green shows singly ionized sulfur, and red indicates doubly ionized oxygen. Credit: NASA, ESA, J. Hester and A. Loll (Arizona State University)


Reference: Teruaki Enoto, Toshio Terasawa, Shota Kisaka, Chin-Ping Hu, Sebastien Guillot, Natalia Lewandowska, Christian Malacaria, Paul S. Ray, Wynn C.G. Ho, Alice K. Harding, Takashi Okajima, Zaven Arzoumanian, Keith C. Gendreau, Zorawar Wadiasingh, Craig B. Markwardt, Yang Soong, Steve Kenyon, Slavko Bogdanov, Walid A. Majid, Tolga Güver, Gaurava K. Jaisawal, Rick Foster, Yasuhiro Murata, Hiroshi Takeuchi, Kazuhiro Takefuji, Mamoru Sekido, Yoshinori Yonekura, Hiroaki Misawa, Fuminori Tsuchiya, Takahiko Aoki, Munetoshi Tokumaru, Mareki Honma, Osamu Kameya, Tomoaki Oyama, Katsuaki Asano, Shinpei Shibata, Shuta J. Tanaka, “Enhanced x-ray emission coinciding with giant radio pulses from the Crab Pulsar”, Science  09 Apr 2021: Vol. 372, Issue 6538, pp. 187-190 DOI: 10.1126/science.abd4659


Provided by NASA Goddard

New Research Shows That Mars Did Not Dry Up All At Once (Planetary Science)

Mars had dry and wet eras and dried up for good 3 billion years ago

“A primary goal of the Curiosity mission was to study the transition between the habitable environment of the past, to the dry and cold climate that Mars has now. These rock layers recorded that change in great detail.

– Roger Wiens

While attention has been focused on the Perseverance rover that landed on Mars last month, its predecessor Curiosity continues to explore the base of Mount Sharp on the red planet and is still making discoveries. Research published today in the journal Geology shows that Mars had drier and wetter eras before drying up completely about 3 billion years ago.

“A primary goal of the Curiosity mission was to study the transition between the habitable environment of the past, to the dry and cold climate that Mars has now. These rock layers recorded that change in great detail,” said Roger Wiens, a coauthor on the paper and scientist at Los Alamos National Laboratory, where he is on the ChemCam team. ChemCam is the rock-vaporizing laser that sits on the mast of the Curiosity rover and analyzes the chemical composition of rocks on Mars.

William Rapin, a researcher with the French National Centre for Scientific Research (CNRS), led the study.

Using the long-range camera on ChemCam to make detailed observations of the steep terrain of Mount Sharp, a team including Wiens and other researchers at Los Alamos discovered that the Martian climate alternated between dry and wetter periods before it went completely dry. Spacecraft in orbit around Mars had previously provided clues about the mineral composition of the slopes of Mount Sharp. Now, ChemCam has successfully made detailed observations of the sedimentary beds from the planet’s surface, revealing the conditions under which they formed.  

Moving up through the terrain, Curiosity observed that the types of bed change drastically. Lying above the lake-deposited clays that form the base of Mount Sharp, sandstone layers show structures indicating their formation from wind-formed dunes, suggesting long, dry climate episodes. Higher up still, thin alternating brittle and resistant beds are typical of river floodplain deposits, marking the return of wetter conditions.

These changes in terrain show that the climate of Mars underwent several large-scale fluctuations between wetter and dryer periods, until the generally arid conditions observed today took hold. During its extended mission, Curiosity is scheduled to climb the foothills of Mount Sharp and drill into its various beds for a closer look at these fascinating materials.  

The ChemCam laser instrument uses an infrared-colored laser beam, which heats rock fragments to around 18,000 degrees Fahrenheit (10,000 degrees Celsius), vaporizing them. The plasma produced by this process allows scientists to analyze the chemical and mineral composition of the rocks, which convey important information about the geological history of Mars. The instrument also has a high-resolution camera. ChemCam is commanded alternately from Los Alamos in New Mexico and the French Space Agency in Toulouse, as a partnership between Los Alamos National Laboratory and the IRAP research center. Every week, the operations change hands between the two places. Together, the ChemCam team has published over 100 scientific papers on its discoveries from more than 850,000 laser zaps.

Featured image: View of the slopes of Mount Sharp, showing the various types of terrain that have been and will be explored by the Curiosity rover. The sedimentary structures observed by ChemCam’s telescopic images (mosaics A and B) reveal clues about the ancient environments in which they formed. CREDIT: NASA/JPL-Caltech/MSSS/CNES/CNRS/LANL/IRAP/IAS/LPGN


The paper: W. Rapin, G. Dromart, D. Rubin, L. Le Deit, N. Mangold, L.A. Edgar, O. Gasnault, K. Herkenhoff, S. Le Mouélic, R.B. Anderson, S. Maurice, V. Fox, B.L. Ehlmann, J.L. Dickson, R.C. Wiens; Alternating wet and dry depositional environments recorded in the stratigraphy of Mount Sharp at Gale crater, Mars. Geology 2021; doi: https://doi.org/10.1130/G48519.1


Provided by Los Alamos National Laboratory

What Are The Effects of Dark Matter On the Inspiral Properties of the Binary Neutron Star? (Planetary Science)

The binary neutron star (BNS) in its inspiral phase tidally interact with each other, which affects their stellar structure. Each star’s tidal property depends on the macroscopic properties, such as mass M, radius R, second Love number k2 etc. which are all model-dependent.

Now, Das and colleagues studied the properties of the binary neutron star (BNS) systems in the inspiral phase. To calculate the equation of state (EOS) of the neutron star (NS), they take the relativistic mean-field (RMF) model. The RMF model, namely NL3 (stiff) and two extended RMF model IOPB-I (less stiff) and G3 (soft) are taken to explore the properties of the NS.

They assumed that the dark matter (DM) particles are accreted inside the NS due to its enormous gravitational field. Different macroscopic properties of the NS such as mass M, radius R, tidal deformability λ and dimensionless tidal deformability Λ are calculated at different DM fractions. They found that with the addition of DM inside the NS, the value of the quantities like M, R, λ and Λ decreases.

FIG. 1. (colour online) (2,2) mode waveform, frequency, phase and PN-parameters are shown for three (NL3, G3 and IOPB-I) parameter sets of the EMBNS in the retarded time interval calculated for D = 100 Mpc. © Das et al.

To explore the BNS properties in the inspiral phase, they also considered post-Newtonian (PN) formalism because it is suitable up to the last orbits in the inspiral phase. They calculated the strain amplitude of the polarization waveforms h+ and h×, (2,2) mode waveform h22, orbital phase Φ, frequency of the gravitational wave f and PN parameter x with DM as an extra candidate inside the NS..

“We find that the BNS with soft EOS sustains more time in their inspiral phase as compare to stiff EOS. In the case of DM admixed NS, the BNS with high DM fractions survives more time in the inspiral phase than lesser fraction of DM. The magnitude of f, Φ and x are almost the same for all the assumed parameter sets, but their inspiral time in the last orbit is different. We find a significant change in the BNS systems properties in the inspiral phase with DM inside the NS.”

— told Das, first author of the study.

They found that stiff EOS, like NL3, predicts higher mass and tidal deformability compared to the soft EOS like G3. Therefore, the massive NS easily deformed by the presence of tidal fields created by its companion star. Hence, a less massive BNS system sustains a longer time than a more massive BNS system in the inspiral phase. This is because the tidal interactions accelerate the orbital evolution in the late inspiral phases due to increase in the interactions forces between two NSs.

FIG. 2. (colour online) Same as Fig. 1, but for DM admixed NS with IOPB-I parameter set as a representative case. © Das et al.

Furthermore, they found that, with the addition of DM inside the NS, the inspiral properties such as h22, f, Φ and x are changing significantly (as shown in Fig. 2). The BNS with IOPB-I+DM5 sustains more time in the inspiral orbits as compare to IOPB-I+DM3. The magnitude of f, Φ and x are almost the same, but their inspiral time is different. Therefore, they concluded that DM has significant effects on inspiral properties of BNS.


Reference: H. C. Das, Ankit Kumar, S. K. Patra, “Effects of dark matter on the inspiral properties of the binary neutron star”, ArXiv, pp. 1-10, 2021. https://arxiv.org/abs/2104.01815


Copyright of this article totally belongs to our author S. Aman. One is allowed to reuse it only by giving proper credit either to him or to us

Research Gives New Insight Into Formation Of the Human Embryo (Biology)

Pioneering research led by experts from the University of Exeter’s Living Systems Institute has provided new insight into formation of the human embryo. 

The team of researchers discovered an unique regenerative property of cells in the early human embryo. 

The first tissue to form in the embryo of mammals is the trophectoderm, which goes on to connect with the uterus and make the placenta. Previous research in mice found that trophectoderm is only made once. 

In the new study, however, the research team found that human early embryos are able to regenerate trophectoderm. They also showed that human embryonic stem cells grown in the laboratory can similarly continue to produce trophectoderm and placental cell types. 

These findings show unexpected flexibility in human embryo development and may directly benefit assisted conception (IVF) treatments. In addition, being able to produce early human placental tissue opens a door to finding causes of infertility and miscarriage.  

The study is published in the leading international peer-review journal Cell Stem Cell on Wednesday, April 7th 2021. 

Dr Ge Guo, lead author of the study from the Living Systems Institute said: “We are very excited to discover that human embryonic stem cells can make every type of cell required to produce a new embryo.”  

Professor Austin Smith, Director of the Living Systems Institute and co-author of the study added, said: “Before Dr Guo showed me her results, I did not imagine this should be possible. Her discovery changes our understanding of how the human embryo is made and what we may be able do with human embryonic stem cells” 

Human naïve epiblast cells possess unrestricted lineage potential is published in Cell Stem Cell. 

The research was funded by the Medical Research Council (MRC) .

Featured image: Pioneering research by experts from the Living Systems Institute has provided new insight into formation of the human embryo. © University of Exeter


Reference: Ge Guo, Giuliano Giuseppe Stirparo, Stanley E. Strawbridge, Daniel Spindlow, Jian Yang, James Clarke, Anish Dattani, Ayaka Yanagida, Meng Amy Li, Sam Myers, Buse Nurten Özel, Jennifer Nichols, Austin Smith, Human naive epiblast cells possess unrestricted lineage potential, Cell Stem Cell, 2021, , ISSN 1934-5909, https://doi.org/10.1016/j.stem.2021.02.025. (https://www.sciencedirect.com/science/article/pii/S193459092100076X)


Provided by University of Exeter

Research Shows Cytonemes Distribute Wnt Proteins in Vertebrate Tissue (Medicine)

Scientists have made a pivotal breakthrough in understanding the way in which cells communicate with each other. 

A team of international researchers, including experts from the University of Exeter’s Living Systems Institute, has identified how signalling pathways of Wnt proteins – which orchestrate and control many cell developmental processes – operate on both molecular and cellular levels. 

Various mechanisms exist for cells to communicate with each other, and many are essential for development. This information exchange between cells is often based on signalling proteins that activate specific intracellular signalling cascades to control cell behaviour at a distance.  

Wnt proteins are produced by a relatively small group of cells and orchestrate cell proliferation and differentiation, but also cell movement and polarity of the neighbouring cells.  

However, one of the most crucial functions of the Wnt signalling is patterning of the body axis – which essentially helps determine where the head and tail should form in in a developing tissue.  

Previous research led by Professor Steffen Scholpp, from the Living Systems Institute, highlighted that thin finger-like protrusions, known as cytonemes, carry Wnts from the source cells to recipient cells.  

However, the mechanism controlling Wnt cytonemes at the molecular level is currently unknown. 

In the new study, his team explored the role of a key component of the PCP signalling pathway Vangl2 in zebrafish embryos.  

In this project, Dr Lucy Brunt, identified that Wnt proteins activate the PCP pathway in a source cell in order to regulate cytoneme initiation and signal dissemination.  

By activating this pathway via Vangl2, she induced the formation of long and branched cytonemes which reinforced distant Wnt signalling in the neighbouring cells.  

Based on these data, fellow researcher Dr Kyle Wedgwood and his team developed a mathematical model to simulate this effect in a developing zebrafish egg, and predicted that the patterning of the body axis is massively altered.  

“And the prediction was correct” explained Dr Brunt. “ We found that the formation of longer cytonemes in zebrafish larvae led to a strongly reduced head, and strikingly the forebrain tissue was missing completely.” 

Together with cell biologists from the National University of Singapore, the scientists showed that the mechanism they described in zebrafish embryogenesis, operates also in different tissues, including  human cancer cells. 

Professor Scholpp said “The exciting results of this multidisciplinary, multiscale project provides a step change in understanding how the Wnt signalling pathway operates at the molecular and cellular level in a living vertebrate animal. 

“The data from this project will help us to understand the mechanisms involved in controlling normal Wnt signalling, in the future,” he added. “We believe that the outcome will have fundamental implications for how we could manipulate Wnt signalling during disease states.”

Featured image: Scientists have made a pivotal breakthrough in understanding the way in which cells communicate with each other. © University of Exeter


Provided by University of Exeter

Acrylamide Derivatives For the Treatment of Rheumatoid Arthritis (Medicine)

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS).

The authors designed and synthesized a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53?55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively.

The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

Featured image: Dihydroorotate dehydrogenase (DHODH) is an attracting target for the treatment of immunological diseases. A series of acrylamide-based novel DHODH inhibitors as potential rheumatoid arthritis (RA) treatment agents were designed and synthesized, among which 54 is the most potent one with good pharmacokinetic profiles and favorable in vivo anti-arthritic effects. © Acta Pharmaceutica Sinica B


Article reference: Fanxun Zeng, Shiliang Li, Guantian Yang, Yating Luo, Tiantian Qi, Yingfan Liang, Tingyuan Yang, Letian Zhang, Rui Wang, Lili Zhu, Honglin Li, Xiaoyong Xu, Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis, Acta Pharmaceutica Sinica B, 2021, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2020.10.008 https://www.sciencedirect.com/science/article/pii/S2211383520307590?via%3Dihub


Provided by Compuscript Ltd

How People Decide When They Have So Many Choices? (Psychology)

Study used eye-trackers to see how people selected snack foods

It’s one thing to decide among two or three snacks available at a friend’s house. But what do people do when they’re faced with a vending machine offering 36 different options?

A new study using eye-tracking technology suggests that the amount of time people spend looking at individual items may actually help them decide. Findings showed that people tended to choose snacks they spent more time looking at, sometimes even over snacks that they rated more highly.

“We could do pretty well predicting what people would choose based just on their ratings of the snacks available to them. But we could do an even better job by accounting for how much they looked at each item,” said Ian Krajbich, co-author of the study and associate professor of psychology and economics at The Ohio State University.

Ian Krajbich © OSU

But the amount of time people spend looking at individual items isn’t the whole story of how people decide when they have many alternatives, Krajbich said.

“It’s a little more complicated than that,” he said.

Krajbich conducted the study with lead author Armin Thomas of Technische Universität Berlin and Felix Molter of Freie Universität Berlin. The research was published this week in the journal eLife.

The study involved 49 people who said they were fans of snack foods and who agreed to fast for at least four hours before the study – to make sure the task was relevant to them.

On a computer screen, the participants were shown sets of 9, 16, 25 or 36 different snack foods and asked to choose which snack they would like to eat the most at the end of the experiment.

They did this multiple times over the course of the experiment. An eye tracker recorded exactly where they looked while making these choices.

After the experiments, participants rated how much they liked all 80 snacks that were part of the study.

The results showed that people didn’t look carefully at all the items before making a choice, or even just look at each item until they found one of their favorites. Instead, they looked around in a way that at first glance looked random, but depended on the physical location of the items as well as how much they were liked.

“There is this peripheral screening process where people learn to avoid even looking directly at the snacks they don’t really like,” Krajbich said.

“This is not something that we see in studies where participants only have two alternatives. It only occurs when they have lots of options.”

One of the leading theories among researchers is that when people are presented with many choices, they scan until they find something that is “good enough” – in this case a snack they will enjoy, regardless of whether it is their favorite.

But that’s not what happened, Krajbich said. If this “satisficing” model were true, people would quit looking as soon as they found a snack that was good enough. But results showed that participants chose the last snack they looked at only about 45% of the time.

Instead, what seemed to happen most often is that people would look through the items, often going back and forth between them, until one item stood out from the others – often the snack they looked at the most.

“People made a choice when they concluded the best option was sufficiently better than the next-best option,” he said.

Where the snacks appeared in the display – left or right, top or bottom – didn’t play much of a role in people’s decision-making. Participants often started searching in the top left of the display and then looked left to right, top to bottom – but only to a limited extent.

“Pretty quickly their attention gets drawn to their higher-value options. That influences their search process and their gaze starts to jump around less predictably,” he said.

Featured image: How do you decide when you have so many choices? © OSU


Reference: Armin Thomas et al., “Uncovering the computational mechanisms underlying many-alternative choice”, eLife, 2021. DOI: 10.7554/eLife.57012 https://elifesciences.org/articles/57012


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