Francesca Mattiroli
@fmattiroli.bsky.social
Biochemist and structural biologist with a love for chromatin. Group leader at the Hubrecht Institute.
Pinned
Some (+)ve news to lighten another heavy weekend: our latest preprint (c/o Mattiroli + Ramani labs) is up!
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers
DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...
www.biorxiv.org
The latest work from ours and @vram142.bsky.social lab is out! True teamwork to visualize nascent chromatin with strand resolution, using a fully reconstituted system. Very proud of superstar-PhD student Bruna, and @palindromephd.bsky.social. Learning so much from Vijay’s amazing technologies! RT
Reposted by Francesca Mattiroli
Very excited to present OpenCGChromatin🔥🔥🔥
A new coarse-grained model that probes full chromatin condensates at near-atomistic resolution to reveal the molecular regulation of chromatin structure and phase separation
Brilliantly led by @kieran-russell.bsky.social, with the Rosen and Orozco groups
A new coarse-grained model that probes full chromatin condensates at near-atomistic resolution to reveal the molecular regulation of chromatin structure and phase separation
Brilliantly led by @kieran-russell.bsky.social, with the Rosen and Orozco groups
November 18, 2025 at 3:07 PM
Very excited to present OpenCGChromatin🔥🔥🔥
A new coarse-grained model that probes full chromatin condensates at near-atomistic resolution to reveal the molecular regulation of chromatin structure and phase separation
Brilliantly led by @kieran-russell.bsky.social, with the Rosen and Orozco groups
A new coarse-grained model that probes full chromatin condensates at near-atomistic resolution to reveal the molecular regulation of chromatin structure and phase separation
Brilliantly led by @kieran-russell.bsky.social, with the Rosen and Orozco groups
Reposted by Francesca Mattiroli
📢 Last days to apply! 📢
Fully funded PhD position, starting Oct 2026.
Deadline Nov 16th.
We provide a supportive environment and top notch facilities, helping you develop into an independent scientist.
Project details: tinyurl.com/CosterPhD
Apply: tinyurl.com/ApplyICR
The lab: CosterLab.com
Fully funded PhD position, starting Oct 2026.
Deadline Nov 16th.
We provide a supportive environment and top notch facilities, helping you develop into an independent scientist.
Project details: tinyurl.com/CosterPhD
Apply: tinyurl.com/ApplyICR
The lab: CosterLab.com
Typos in the genome: Defining the molecular mechanism of replication slippage
Typos in the genome: Defining the molecular mechanism of replication slippage
tinyurl.com
November 14, 2025 at 1:04 PM
📢 Last days to apply! 📢
Fully funded PhD position, starting Oct 2026.
Deadline Nov 16th.
We provide a supportive environment and top notch facilities, helping you develop into an independent scientist.
Project details: tinyurl.com/CosterPhD
Apply: tinyurl.com/ApplyICR
The lab: CosterLab.com
Fully funded PhD position, starting Oct 2026.
Deadline Nov 16th.
We provide a supportive environment and top notch facilities, helping you develop into an independent scientist.
Project details: tinyurl.com/CosterPhD
Apply: tinyurl.com/ApplyICR
The lab: CosterLab.com
Reposted by Francesca Mattiroli
Chromatin fatigue: DNA repair alters the chromatin environment and introduces heritable variation in gene expression in a larger region around the lesion! Amazing achievement by @sbantele.bsky.social and Jiri Lukas published in @science.org 🙌 Happy we could contribute. See 👇
𝗖𝗮𝗻 𝗰𝗲𝗹𝗹𝘀 𝗲𝘃𝗲𝗿 𝘁𝗿𝘂𝗹𝘆 𝗿𝗲𝗰𝗼𝘃𝗲𝗿 𝗳𝗿𝗼𝗺 𝗗𝗡𝗔 𝗱𝗮𝗺𝗮𝗴𝗲?Excited to share our new study “Repair of DNA double-strand breaks leaves heritable impairment to genome function”, revealing DNA repair’s hidden cost, out now @science.org tinyurl.com/5n6zw3ye. Led by @sbantele.bsky.social and Jiri Lukas.🧵👇1/n
Repair of DNA double-strand breaks leaves heritable impairment to genome function
Upon DNA breakage, a genomic locus undergoes alterations in three-dimensional chromatin architecture to facilitate signaling and repair. Although cells possess mechanisms to repair damaged DNA, it is ...
tinyurl.com
November 12, 2025 at 3:55 AM
Chromatin fatigue: DNA repair alters the chromatin environment and introduces heritable variation in gene expression in a larger region around the lesion! Amazing achievement by @sbantele.bsky.social and Jiri Lukas published in @science.org 🙌 Happy we could contribute. See 👇
Beautiful work!!
𝗖𝗮𝗻 𝗰𝗲𝗹𝗹𝘀 𝗲𝘃𝗲𝗿 𝘁𝗿𝘂𝗹𝘆 𝗿𝗲𝗰𝗼𝘃𝗲𝗿 𝗳𝗿𝗼𝗺 𝗗𝗡𝗔 𝗱𝗮𝗺𝗮𝗴𝗲?Excited to share our new study “Repair of DNA double-strand breaks leaves heritable impairment to genome function”, revealing DNA repair’s hidden cost, out now @science.org tinyurl.com/5n6zw3ye. Led by @sbantele.bsky.social and Jiri Lukas.🧵👇1/n
Repair of DNA double-strand breaks leaves heritable impairment to genome function
Upon DNA breakage, a genomic locus undergoes alterations in three-dimensional chromatin architecture to facilitate signaling and repair. Although cells possess mechanisms to repair damaged DNA, it is ...
tinyurl.com
November 7, 2025 at 12:23 PM
Beautiful work!!
This is really great news for the Dutch structural biology community, a much needed upgrade of the national EM infrastructure. Thank you Friedrich and the many others who put in a lot of work to make this a reality!
Very happy that NWO supports this major upgrade of our national EM infrastructure. It is great that this initiative got broad support all over NL, and it will EMPower fantastic science - looking forward to that!
www.uu.nl/en/news/33-m...
www.uu.nl/en/news/33-m...
33 million euro investment for national electron microscope facility EMPower
A major new national facility for electron microscopy, called EMPower, has been awarded to a consortium of Dutch universities and medical centers. EMPower aims to pave the way for major discoveries im...
www.uu.nl
November 4, 2025 at 8:12 PM
This is really great news for the Dutch structural biology community, a much needed upgrade of the national EM infrastructure. Thank you Friedrich and the many others who put in a lot of work to make this a reality!
Reposted by Francesca Mattiroli
Very happy that NWO supports this major upgrade of our national EM infrastructure. It is great that this initiative got broad support all over NL, and it will EMPower fantastic science - looking forward to that!
www.uu.nl/en/news/33-m...
www.uu.nl/en/news/33-m...
33 million euro investment for national electron microscope facility EMPower
A major new national facility for electron microscopy, called EMPower, has been awarded to a consortium of Dutch universities and medical centers. EMPower aims to pave the way for major discoveries im...
www.uu.nl
November 4, 2025 at 7:14 AM
Very happy that NWO supports this major upgrade of our national EM infrastructure. It is great that this initiative got broad support all over NL, and it will EMPower fantastic science - looking forward to that!
www.uu.nl/en/news/33-m...
www.uu.nl/en/news/33-m...
Reposted by Francesca Mattiroli
I'm excited to share our work on the regulation of endomitosis in worm intestines:
www.biorxiv.org/content/10.1...
We find that cells are able to uncouple nuclear division from cell division by transcriptional repression of key cytokinesis regulators
www.biorxiv.org/content/10.1...
We find that cells are able to uncouple nuclear division from cell division by transcriptional repression of key cytokinesis regulators
Transcriptional repression of central spindle factors controls endomitosis in the C. elegans intestine
During development, many cell types transition from canonical to non-canonical cell cycles, suchas endomitosis and endoreplication, in which they duplicate their DNA but do not divide, giving rise to ...
www.biorxiv.org
August 5, 2025 at 10:27 AM
I'm excited to share our work on the regulation of endomitosis in worm intestines:
www.biorxiv.org/content/10.1...
We find that cells are able to uncouple nuclear division from cell division by transcriptional repression of key cytokinesis regulators
www.biorxiv.org/content/10.1...
We find that cells are able to uncouple nuclear division from cell division by transcriptional repression of key cytokinesis regulators
Reposted by Francesca Mattiroli
John Gurdon, former Group Leader and Head of @cellbiol-mrclmb.bsky.social has died.
Despite calling himself a "total non-intellectual” his work to reprogramme somatic cells to pluripotent stem cells transformed the field of developmental biology.
More: www2.mrc-lmb.cam.ac.uk/john-gurdon-...
#LMBNews
Despite calling himself a "total non-intellectual” his work to reprogramme somatic cells to pluripotent stem cells transformed the field of developmental biology.
More: www2.mrc-lmb.cam.ac.uk/john-gurdon-...
#LMBNews
October 8, 2025 at 8:49 AM
John Gurdon, former Group Leader and Head of @cellbiol-mrclmb.bsky.social has died.
Despite calling himself a "total non-intellectual” his work to reprogramme somatic cells to pluripotent stem cells transformed the field of developmental biology.
More: www2.mrc-lmb.cam.ac.uk/john-gurdon-...
#LMBNews
Despite calling himself a "total non-intellectual” his work to reprogramme somatic cells to pluripotent stem cells transformed the field of developmental biology.
More: www2.mrc-lmb.cam.ac.uk/john-gurdon-...
#LMBNews
Reposted by Francesca Mattiroli
Save the date! The second Hubrecht Symposium will take place on March 26, 2026. This year’s theme is “Molecular Machines in Development”, with Petra Hajkova, Andrea Pauli and @danielgerlich.bsky.social as keynote speakers. Registration opens soon, stay tuned via hubrecht.eu/hubrecht-symposium/.
October 7, 2025 at 11:10 AM
Save the date! The second Hubrecht Symposium will take place on March 26, 2026. This year’s theme is “Molecular Machines in Development”, with Petra Hajkova, Andrea Pauli and @danielgerlich.bsky.social as keynote speakers. Registration opens soon, stay tuned via hubrecht.eu/hubrecht-symposium/.
Reposted by Francesca Mattiroli
⚠️ Paper alert: Using a novel CRISPR screening approach, we mapped the entire regulatory network controlling Xist—key for X-chromosome inactivation.
👉 We discover how sex and development signals are decoded at a single gene locus.
www.nature.com/articles/s41...
👇 Bluetorial
👉 We discover how sex and development signals are decoded at a single gene locus.
www.nature.com/articles/s41...
👇 Bluetorial
Reporter CRISPR screens decipher cis-regulatory and trans-regulatory principles at the Xist locus - Nature Structural & Molecular Biology
Here Schwämmle et al. develop CRISPR reporter screens to map transcription-factor-regulatory element interactions at the Xist locus, revealing a two-step mechanism integrating developmental and X-dosage signals to initiate X-chromosome inactivation.
www.nature.com
October 6, 2025 at 1:02 PM
⚠️ Paper alert: Using a novel CRISPR screening approach, we mapped the entire regulatory network controlling Xist—key for X-chromosome inactivation.
👉 We discover how sex and development signals are decoded at a single gene locus.
www.nature.com/articles/s41...
👇 Bluetorial
👉 We discover how sex and development signals are decoded at a single gene locus.
www.nature.com/articles/s41...
👇 Bluetorial
Reposted by Francesca Mattiroli
Today I am so pleased to present our work on how chromatin remodelers affect mesoscale chromatin organization.
www.science.org/doi/10.1126/...
www.science.org/doi/10.1126/...
ATP-dependent remodeling of chromatin condensates reveals distinct mesoscale outcomes
Adenosine triphosphate (ATP)–dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. We investigate effects of two major remod...
www.science.org
October 2, 2025 at 10:55 PM
Today I am so pleased to present our work on how chromatin remodelers affect mesoscale chromatin organization.
www.science.org/doi/10.1126/...
www.science.org/doi/10.1126/...
Reposted by Francesca Mattiroli
Next week GIIN webinar will feature @fmattiroli.bsky.social and Marco Tigano. Join us on Tuesday, October 7th at 5 PM Rome / 11 AM NYC via zoom: uniroma1.zoom.us/j/95149984403
Register here to become part of our community: docs.google.com/forms/d/e/1F...
Register here to become part of our community: docs.google.com/forms/d/e/1F...
September 30, 2025 at 5:24 PM
Next week GIIN webinar will feature @fmattiroli.bsky.social and Marco Tigano. Join us on Tuesday, October 7th at 5 PM Rome / 11 AM NYC via zoom: uniroma1.zoom.us/j/95149984403
Register here to become part of our community: docs.google.com/forms/d/e/1F...
Register here to become part of our community: docs.google.com/forms/d/e/1F...
Join us at the Hubrecht Institute in Utrecht to start your research group! Fantastic scientific environment, strong support, and nice colleagues :) Apply and please share broadly in your network.
Ready to establish your own research group at the Hubrecht Institute for Molecular and Developmental Biology? We’re seeking a tenure-track group leader to develop an innovative research line within our vibrant scientific community. Learn more & apply! https://f.mtr.cool/jncxfqkuds
September 28, 2025 at 9:43 AM
Join us at the Hubrecht Institute in Utrecht to start your research group! Fantastic scientific environment, strong support, and nice colleagues :) Apply and please share broadly in your network.
Teamwork at its best!! Thank you Vijay, for sharing your technologies and computational talent, for the fun discussions and work together, at random hours of the day or night 😃
Will end w/ huge thank you to @fmattiroli.bsky.social & her team, esp Bruna, who spent time w/ us in SF thx to EMBO fellowship. This work exists bc of *international collaboration* & hard work across big time zone gap. We need MORE of this in the world, not LESS for the love of god.(7/7)
September 21, 2025 at 7:25 AM
Teamwork at its best!! Thank you Vijay, for sharing your technologies and computational talent, for the fun discussions and work together, at random hours of the day or night 😃
Reposted by Francesca Mattiroli
(2) we observe intrinsic asymmetry in single-molecule fiber structures assembled on lagging and leading strands. This is neither resolved by CAF-1/ASF1, nor addition of active ISWI remodeler (Isw1a). Will be exciting to identify the factors that restore symmetry in reconstituted setting!(6/n)
September 20, 2025 at 4:10 PM
(2) we observe intrinsic asymmetry in single-molecule fiber structures assembled on lagging and leading strands. This is neither resolved by CAF-1/ASF1, nor addition of active ISWI remodeler (Isw1a). Will be exciting to identify the factors that restore symmetry in reconstituted setting!(6/n)
Reposted by Francesca Mattiroli
Some (+)ve news to lighten another heavy weekend: our latest preprint (c/o Mattiroli + Ramani labs) is up!
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers
DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...
www.biorxiv.org
September 20, 2025 at 4:10 PM
Some (+)ve news to lighten another heavy weekend: our latest preprint (c/o Mattiroli + Ramani labs) is up!
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
The latest work from ours and @vram142.bsky.social lab is out! True teamwork to visualize nascent chromatin with strand resolution, using a fully reconstituted system. Very proud of superstar-PhD student Bruna, and @palindromephd.bsky.social. Learning so much from Vijay’s amazing technologies! RT
Some (+)ve news to lighten another heavy weekend: our latest preprint (c/o Mattiroli + Ramani labs) is up!
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)
The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers
DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...
www.biorxiv.org
September 21, 2025 at 7:12 AM
The latest work from ours and @vram142.bsky.social lab is out! True teamwork to visualize nascent chromatin with strand resolution, using a fully reconstituted system. Very proud of superstar-PhD student Bruna, and @palindromephd.bsky.social. Learning so much from Vijay’s amazing technologies! RT
Do not miss this opportunity!! Incredible science and mentor!
Are you interested in working on related projects? 🌱
The Knipscheer lab at the Hubrecht Institute (Utrecht, the Netherlands) has openings for a postdoc and a PhD position.
Apply here: www.hubrecht.eu/jobs
The Knipscheer lab at the Hubrecht Institute (Utrecht, the Netherlands) has openings for a postdoc and a PhD position.
Apply here: www.hubrecht.eu/jobs
September 19, 2025 at 9:51 PM
Do not miss this opportunity!! Incredible science and mentor!
Check this out from our colleagues! Congratulations!
1/ 🧵 I am excited to share a new preprint from our group:
Single-cell Dam&T-seq during mouse corticogenesis reveals how genome–lamina interactions regulate long neuronal genes.
doi.org/10.1101/2025...
#Neurodevelopment #Epigenetics @hubrechtinstitute.bsky.social @oncodeinstitute.bsky.social
Single-cell Dam&T-seq during mouse corticogenesis reveals how genome–lamina interactions regulate long neuronal genes.
doi.org/10.1101/2025...
#Neurodevelopment #Epigenetics @hubrechtinstitute.bsky.social @oncodeinstitute.bsky.social
MeCP2 binding and genome–lamina reorganization precede long gene activation during mouse corticogenesis
During corticogenesis, neural gene expression is tightly coordinated by chromatin and epigenetic changes, whose misregulation can lead to neurodevelopmental disorders[1][1]–[4][2]. The role of spatial...
doi.org
September 19, 2025 at 5:09 AM
Check this out from our colleagues! Congratulations!
Reposted by Francesca Mattiroli
We thank Diego Dibitetto and @polosophie.bsky.social for sharing their research with the GIIN community today!
Our next seminar will take place on Tuesday, October 7th featuring @fmattiroli.bsky.social and Marco Tigano.
Subscribe here to join our mailing list: docs.google.com/forms/d/e/1F...
Our next seminar will take place on Tuesday, October 7th featuring @fmattiroli.bsky.social and Marco Tigano.
Subscribe here to join our mailing list: docs.google.com/forms/d/e/1F...
September 9, 2025 at 8:51 PM
We thank Diego Dibitetto and @polosophie.bsky.social for sharing their research with the GIIN community today!
Our next seminar will take place on Tuesday, October 7th featuring @fmattiroli.bsky.social and Marco Tigano.
Subscribe here to join our mailing list: docs.google.com/forms/d/e/1F...
Our next seminar will take place on Tuesday, October 7th featuring @fmattiroli.bsky.social and Marco Tigano.
Subscribe here to join our mailing list: docs.google.com/forms/d/e/1F...
Check this out!!
Featuring #AlphaBridge features from @alvarezsalmoral.bsky.social, with @jonasteuwen.bsky.social and team, our new work from @nkinl.bsky.social nl.bsky.social @oncodeinstitute.bsky.social . Have a look at ahmpc.eu for more!
Integrating computational protein structure predictions and genetic dependencies yields an atlas of human multi-protein complexes (AHMPC) https://www.biorxiv.org/content/10.1101/2025.09.09.675133v1
September 13, 2025 at 12:49 PM
Check this out!!
Reposted by Francesca Mattiroli
Preprint alert!
We combined microfluidics, proteomics, and RNA-seq to map spatiotemporal protein expression during mouse somitogenesis and found a novel regulatory strategy: dynamic antagonistic gradients fine-tune signalling strength.
doi.org/10.1101/2025...
We combined microfluidics, proteomics, and RNA-seq to map spatiotemporal protein expression during mouse somitogenesis and found a novel regulatory strategy: dynamic antagonistic gradients fine-tune signalling strength.
doi.org/10.1101/2025...
September 9, 2025 at 4:05 PM
Preprint alert!
We combined microfluidics, proteomics, and RNA-seq to map spatiotemporal protein expression during mouse somitogenesis and found a novel regulatory strategy: dynamic antagonistic gradients fine-tune signalling strength.
doi.org/10.1101/2025...
We combined microfluidics, proteomics, and RNA-seq to map spatiotemporal protein expression during mouse somitogenesis and found a novel regulatory strategy: dynamic antagonistic gradients fine-tune signalling strength.
doi.org/10.1101/2025...
Reposted by Francesca Mattiroli
Together with colleagues at the Dept. of Microsystems Engineering, we are looking for a PhD student to develop methods for femtoliter-scale sample dispensing in cryoEM sample preparation.
edu.nl/h436k
If you like interdisciplinary research & fascinating physics at ultrasmall scales, please apply!
edu.nl/h436k
If you like interdisciplinary research & fascinating physics at ultrasmall scales, please apply!
September 8, 2025 at 1:48 PM
Together with colleagues at the Dept. of Microsystems Engineering, we are looking for a PhD student to develop methods for femtoliter-scale sample dispensing in cryoEM sample preparation.
edu.nl/h436k
If you like interdisciplinary research & fascinating physics at ultrasmall scales, please apply!
edu.nl/h436k
If you like interdisciplinary research & fascinating physics at ultrasmall scales, please apply!
Reposted by Francesca Mattiroli
The @NYTimes has done a fantastic job on explaining what the Trump administration’s savage
cuts to biomedical research mean: cures that won’t happen. Please share this widely. This is a catastrophe. www.nytimes.com/2025/08/24/o...
cuts to biomedical research mean: cures that won’t happen. Please share this widely. This is a catastrophe. www.nytimes.com/2025/08/24/o...
Opinion | America First? Not When It Comes to Your Health.
www.nytimes.com
August 24, 2025 at 4:10 PM
The @NYTimes has done a fantastic job on explaining what the Trump administration’s savage
cuts to biomedical research mean: cures that won’t happen. Please share this widely. This is a catastrophe. www.nytimes.com/2025/08/24/o...
cuts to biomedical research mean: cures that won’t happen. Please share this widely. This is a catastrophe. www.nytimes.com/2025/08/24/o...
Reposted by Francesca Mattiroli
It is not always safe to repair DNA Damage. Sometimes, cells "just bypass it".
During DNA replication, repair of lesions on DNA can be dangerous. Cells instead "tolerate" DNA damage and focus on finishing replication.
Read our review and find out why and how: doi.org/10.1016/j.ti...
During DNA replication, repair of lesions on DNA can be dangerous. Cells instead "tolerate" DNA damage and focus on finishing replication.
Read our review and find out why and how: doi.org/10.1016/j.ti...
August 22, 2025 at 11:48 AM
It is not always safe to repair DNA Damage. Sometimes, cells "just bypass it".
During DNA replication, repair of lesions on DNA can be dangerous. Cells instead "tolerate" DNA damage and focus on finishing replication.
Read our review and find out why and how: doi.org/10.1016/j.ti...
During DNA replication, repair of lesions on DNA can be dangerous. Cells instead "tolerate" DNA damage and focus on finishing replication.
Read our review and find out why and how: doi.org/10.1016/j.ti...