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  1. Article ; Online: Chromatin rigidity provides mechanical and genome protection.

    Stephens, Andrew D

    Mutation research

    2020  Volume 821, Page(s) 111712

    Abstract: The nucleus is the organelle in the cell that contains the genome and its associate proteins which is collectively called chromatin. New work has shown that chromatin and its compaction level, dictated largely through histone modification state, provides ...

    Abstract The nucleus is the organelle in the cell that contains the genome and its associate proteins which is collectively called chromatin. New work has shown that chromatin and its compaction level, dictated largely through histone modification state, provides rigidity to protect and stabilize the nucleus. Alterations in chromatin, its mechanics, and downstream loss of nuclear shape and stability are hallmarks of human disease. Weakened nuclear mechanics and abnormal morphology have been shown to cause rupturing of the nucleus which results in nuclear dysfunction including DNA damage. Thus, the rigidity provided by chromatin to maintain nuclear mechanical stability also provides its own protection from DNA damage via compartmentalization maintenance.
    MeSH term(s) Cell Nucleus/physiology ; Chromatin/chemistry ; Chromatin/physiology ; DNA Damage ; DNA Repair ; Genome, Human ; Humans ; Mechanotransduction, Cellular
    Chemical Substances Chromatin
    Language English
    Publishing date 2020-06-17
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 206607-5
    ISSN 1873-135X ; 1383-5718 ; 0027-5107 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    ISSN (online) 1873-135X
    ISSN 1383-5718 ; 0027-5107 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    DOI 10.1016/j.mrfmmm.2020.111712
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Nuclear shape is affected differentially by loss of lamin A, lamin C, or both lamin A and C.

    Pho, Mai / Berrada, Yasmin / Gunda, Aachal / Stephens, Andrew D

    microPublication biology

    2024  Volume 2024

    Abstract: Lamin intermediate filaments form a peripheral meshwork to support nuclear shape and function. Knockout of the LMNA gene that encodes for both lamin A and C results in an abnormally shaped nucleus. To determine the relative contribution of lamin A and C ... ...

    Abstract Lamin intermediate filaments form a peripheral meshwork to support nuclear shape and function. Knockout of the LMNA gene that encodes for both lamin A and C results in an abnormally shaped nucleus. To determine the relative contribution of lamin A and C to nuclear shape, we measured nuclear blebbing and circular deviation in separate lamin A and lamin C knockdown and LMNA-/- stable cells. Lamin A knockdown increased nuclear blebbing while loss of lamin A, C, or both increased circular deviation. Overall, loss of lamin A, lamin C or both lamin A/C affect nuclear shape differentially.
    Language English
    Publishing date 2024-02-16
    Publishing country United States
    Document type Journal Article
    ISSN 2578-9430
    ISSN (online) 2578-9430
    DOI 10.17912/micropub.biology.001103
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  3. Article ; Online: SHAP Model Explainability in ECMO - PAL mortality prediction: A Critical Analysis. Author's reply.

    Stephens, Andrew F / Šeman, Michael / Hodgson, Carol L / Gregory, Shaun D

    Intensive care medicine

    2023  Volume 49, Issue 12, Page(s) 1560–1562

    MeSH term(s) Humans ; Extracorporeal Membrane Oxygenation
    Language English
    Publishing date 2023-10-31
    Publishing country United States
    Document type Letter
    ZDB-ID 80387-x
    ISSN 1432-1238 ; 0340-0964 ; 0342-4642 ; 0935-1701
    ISSN (online) 1432-1238
    ISSN 0340-0964 ; 0342-4642 ; 0935-1701
    DOI 10.1007/s00134-023-07237-y
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  4. Article: Guided Growth for Tibial Recurvatum.

    Stevens, Peter / Stephens, Andrew / Rothberg, David

    Strategies in trauma and limb reconstruction

    2022  Volume 16, Issue 3, Page(s) 172–175

    Abstract: ... A, Rothberg D. Guided Growth for Tibial Recurvatum. Strategies Trauma Limb Reconstr 2021;16(3):172-175. ... III - retrospective case series - no controls.: How to cite this article: Stevens P, Stephens ...

    Abstract Aim and objective: Sagittal guided growth of the distal anterior femur has been shown to be effective for the correction of fixed knee flexion deformity that is encountered in clinical practice. The opposite deformity, namely genu recurvatum, is comparatively uncommon in children. The most common aetiology is post-traumatic. Acute correction by means of osteotomy has significant associated risks. Our objective was to determine whether a posterior 8-plate would suffice in correcting tibial recurvatum and obviate the need for an osteotomy.
    Materials and methods: We included a total of five deformities, three boys (one bilateral) and one girl, managed by means of tethering of the posterior proximal tibial physis with a tension band plate. Standard radiographs obtained preoperatively and at follow-up included a standing anteroposterior (AP) of the legs noting limb lengths and the mechanical axis. We also obtained standing lateral views of each knee in maximal extension to measure and compare the posterior proximal tibial angle (PPTA).
    Results: The same-day surgery was well tolerated and there were no surgical or post-operative complications. The preoperative PPTA ranged from 106° to 117° and averaged 84° at follow-up. Correction occurred in an average of 20 months (range of 18-24 months). The patient with bilateral recurvatum due to Hurler's syndrome developed unilateral recurrent recurvatum culminating in percutaneous reinsertion of the metaphyseal screw. For each patient, knee hyperextension and associated pseudo-laxity resolved and limb lengths remained equal at follow-up.
    Conclusion: Children with progressive genu recurvatum typically present with an insidious onset of symptoms. Guided growth of the posterior proximal tibia is a safe and effective means of correcting the deformity; osteotomy was avoided in this series.
    Level of evidence: III - retrospective case series - no controls.
    How to cite this article: Stevens P, Stephens A, Rothberg D. Guided Growth for Tibial Recurvatum. Strategies Trauma Limb Reconstr 2021;16(3):172-175.
    Language English
    Publishing date 2022-01-24
    Publishing country India
    Document type Journal Article
    ZDB-ID 2387508-2
    ISSN 1828-8928 ; 1828-8936
    ISSN (online) 1828-8928
    ISSN 1828-8936
    DOI 10.5005/jp-journals-10080-1535
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  5. Article ; Online: Modeling of Cell Nuclear Mechanics: Classes, Components, and Applications.

    Hobson, Chad M / Stephens, Andrew D

    Cells

    2020  Volume 9, Issue 7

    Abstract: Cell nuclei are paramount for both cellular function and mechanical stability. These two roles of nuclei are intertwined as altered mechanical properties of nuclei are associated with altered cell behavior and disease. To further understand the ... ...

    Abstract Cell nuclei are paramount for both cellular function and mechanical stability. These two roles of nuclei are intertwined as altered mechanical properties of nuclei are associated with altered cell behavior and disease. To further understand the mechanical properties of cell nuclei and guide future experiments, many investigators have turned to mechanical modeling. Here, we provide a comprehensive review of mechanical modeling of cell nuclei with an emphasis on the role of the nuclear lamina in hopes of spurring future growth of this field. The goal of this review is to provide an introduction to mechanical modeling techniques, highlight current applications to nuclear mechanics, and give insight into future directions of mechanical modeling. There are three main classes of mechanical models-schematic, continuum mechanics, and molecular dynamics-which provide unique advantages and limitations. Current experimental understanding of the roles of the cytoskeleton, the nuclear lamina, and the chromatin in nuclear mechanics provide the basis for how each component is subsequently treated in mechanical models. Modeling allows us to interpret assay-specific experimental results for key parameters and quantitatively predict emergent behaviors. This is specifically powerful when emergent phenomena, such as lamin-based strain stiffening, can be deduced from complimentary experimental techniques. Modeling differences in force application, geometry, or composition can additionally clarify seemingly conflicting experimental results. Using these approaches, mechanical models have informed our understanding of relevant biological processes such as migration, nuclear blebbing, nuclear rupture, and cell spreading and detachment. There remain many aspects of nuclear mechanics for which additional mechanical modeling could provide immediate insight. Although mechanical modeling of cell nuclei has been employed for over a decade, there are still relatively few models for any given biological phenomenon. This implies that an influx of research into this realm of the field has the potential to dramatically shape both future experiments and our current understanding of nuclear mechanics, function, and disease.
    MeSH term(s) Animals ; Cell Nucleus/metabolism ; Chromatin/metabolism ; Cytoskeleton/metabolism ; Humans ; Lamin Type A/metabolism ; Models, Biological ; Nuclear Lamina/metabolism
    Chemical Substances Chromatin ; Lamin Type A
    Language English
    Publishing date 2020-07-06
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9071623
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  6. Article: Nuclear blebs are associated with destabilized chromatin packing domains.

    Pujadas Liwag, Emily M / Acosta, Nicolas / Almassalha, Luay Matthew / Su, Yuanzhe Patrick / Gong, Ruyi / Kanemaki, Masato T / Stephens, Andrew D / Backman, Vadim

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Disrupted nuclear shape is associated with multiple pathological processes including premature aging disorders, cancer-relevant chromosomal rearrangements, and DNA damage. Nuclear blebs (i.e., herniations of the nuclear envelope) have been induced by (1) ...

    Abstract Disrupted nuclear shape is associated with multiple pathological processes including premature aging disorders, cancer-relevant chromosomal rearrangements, and DNA damage. Nuclear blebs (i.e., herniations of the nuclear envelope) have been induced by (1) nuclear compression, (2) nuclear migration (e.g., cancer metastasis), (3) actin contraction, (4) lamin mutation or depletion, and (5) heterochromatin enzyme inhibition. Recent work has shown that chromatin transformation is a hallmark of bleb formation, but the transformation of higher-order structures in blebs is not well understood. As higher-order chromatin has been shown to assemble into nanoscopic packing domains, we investigated if (1) packing domain organization is altered within nuclear blebs and (2) if alteration in packing domain structure contributed to bleb formation. Using Dual-Partial Wave Spectroscopic microscopy, we show that chromatin packing domains within blebs are transformed both by B-type lamin depletion and the inhibition of heterochromatin enzymes compared to the nuclear body. Pairing these results with single-molecule localization microscopy of constitutive heterochromatin, we show fragmentation of nanoscopic heterochromatin domains within bleb domains. Overall, these findings indicate that translocation into blebs results in a fragmented higher-order chromatin structure.
    Summary statement: Nuclear blebs are linked to various pathologies, including cancer and premature aging disorders. We investigate alterations in higher-order chromatin structure within blebs, revealing fragmentation of nanoscopic heterochromatin domains.
    Language English
    Publishing date 2024-03-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.28.587095
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  7. Article ; Online: Use of Sutureless Valve in Aortic Root Enlargement.

    Marasco, Silvana F / Banham, Taylah / Gregory, Shaun D / Vu, Tony / Stephens, Andrew F

    Heart, lung & circulation

    2023  Volume 33, Issue 1, Page(s) 92–98

    Abstract: Aim: The small aortic annulus is a surgical challenge in patients undergoing aortic valve replacement which may lead to patient prosthesis mismatch. Management options include aortic root enlargement, aortic root replacement, and the use of sutureless ... ...

    Abstract Aim: The small aortic annulus is a surgical challenge in patients undergoing aortic valve replacement which may lead to patient prosthesis mismatch. Management options include aortic root enlargement, aortic root replacement, and the use of sutureless valves. In this case series, we report our results with aortic root enlargement, sutureless valve implantation, and benchtop modelling of the radial forces exerted.
    Methods: Five patients underwent aortic root enlargement and insertion of the Perceval valve as part of the management strategy to enlarge their effective orifice area. We further investigate this strategy with a benchtop model to quantify the radial forces exerted by the Perceval valve on the aortic annulus. Radial and hoop forces on the aortic annulus and inner ring of the Perceval valve were recorded using a Mylar force tester.
    Results: Five female patients with native annulus between 18mm-20mm underwent root enlargement and insertion of a Perceval S valve. The postoperative course was uncomplicated for all patients except for one who required a permanent pacemaker insertion. Transvalvular pressure gradients remained low at up to 4 years of follow-up (12 mmHg-21 mmHg), with no evidence of paravalvular leak. Benchtop testing demonstrated radial forces exerted at the annulus in all-size Perceval S valves to be within physiological variables, whereas compressive forces required to deform the valves were supraphysiological.
    Conclusions: The deployment of a sutureless valve within a surgical enlarged aortic root is a feasible solution in patients with a small aortic root.
    MeSH term(s) Humans ; Female ; Heart Valve Prosthesis Implantation/methods ; Aorta, Thoracic/surgery ; Bioprosthesis ; Heart Valve Prosthesis ; Aortic Valve/diagnostic imaging ; Aortic Valve/surgery ; Aortic Valve Stenosis/diagnosis ; Aortic Valve Stenosis/surgery ; Prosthesis Design ; Treatment Outcome
    Language English
    Publishing date 2023-12-21
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2020980-0
    ISSN 1444-2892 ; 1443-9506
    ISSN (online) 1444-2892
    ISSN 1443-9506
    DOI 10.1016/j.hlc.2023.10.017
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    Zs.A 4988: Show issues Location:
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  8. Article ; Online: Mechanics and functional consequences of nuclear deformations.

    Kalukula, Yohalie / Stephens, Andrew D / Lammerding, Jan / Gabriele, Sylvain

    Nature reviews. Molecular cell biology

    2022  Volume 23, Issue 9, Page(s) 583–602

    Abstract: As the home of cellular genetic information, the nucleus has a critical role in determining cell fate and function in response to various signals and stimuli. In addition to biochemical inputs, the nucleus is constantly exposed to intrinsic and extrinsic ...

    Abstract As the home of cellular genetic information, the nucleus has a critical role in determining cell fate and function in response to various signals and stimuli. In addition to biochemical inputs, the nucleus is constantly exposed to intrinsic and extrinsic mechanical forces that trigger dynamic changes in nuclear structure and morphology. Emerging data suggest that the physical deformation of the nucleus modulates many cellular and nuclear functions. These functions have long been considered to be downstream of cytoplasmic signalling pathways and dictated by gene expression. In this Review, we discuss an emerging perspective on the mechanoregulation of the nucleus that considers the physical connections from chromatin to nuclear lamina and cytoskeletal filaments as a single mechanical unit. We describe key mechanisms of nuclear deformations in time and space and provide a critical review of the structural and functional adaptive responses of the nucleus to deformations. We then consider the contribution of nuclear deformations to the regulation of important cellular functions, including muscle contraction, cell migration and human disease pathogenesis. Collectively, these emerging insights shed new light on the dynamics of nuclear deformations and their roles in cellular mechanobiology.
    MeSH term(s) Cell Differentiation ; Cell Nucleus/genetics ; Chromatin/metabolism ; Cytoskeleton/metabolism ; Humans ; Signal Transduction
    Chemical Substances Chromatin
    Language English
    Publishing date 2022-05-05
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-022-00480-z
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    Zs.MG 26: Show issues

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  9. Article ; Online: Rare cause of ventricular calcification.

    Stephens, Daniel / Pattock, Andrew / Mayfield, Jacob

    Heart (British Cardiac Society)

    2023  Volume 109, Issue 11, Page(s) 845

    MeSH term(s) Humans ; Echocardiography ; Myocardium ; Magnetic Resonance Imaging
    Language English
    Publishing date 2023-05-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1303417-0
    ISSN 1468-201X ; 1355-6037
    ISSN (online) 1468-201X
    ISSN 1355-6037
    DOI 10.1136/heartjnl-2022-322162
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  10. Article ; Online: Evaluation of Fluoroscopically Guided Transforaminal Selective Nerve Root Sleeve Injections for Lumbar Spinal Stenosis With Radiculopathy Utilizing Patient Reported Outcome Measurement Information System as an Outcome Measure.

    Stephens, Andrew R / El-Hassan, Ramzi / Patel, Rajeev K

    Archives of physical medicine and rehabilitation

    2024  

    Abstract: ... PROMIS (D) v1.0 were collected at baseline and post-procedure short term (<3-months) and long-term (6-12 ...

    Abstract Objective: To evaluate the therapeutic effect of transforaminal selective nerve root sleeve injections (TFSNRIs) in a specific subset of patients with clinical symptoms and presentation consistent with spinal stenosis.
    Design: Retrospective review.
    Setting: Tertiary academic spine center.
    Participants: A total of 176 patients with radicular leg pain with or without low back pain as well as ≥3 clinical features of spinal stenosis and corroborative radiographic features of spinal stenosis on lumbar spine magnetic resonance imaging without confounding spinal pathology (N=176).
    Interventions: Fluoroscopically guided transforaminal selective nerve root sleeve injections.
    Main outcome measures: Patient Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) v1.2/v2.0, Pain Interference (PI) v1.1, and PROMIS (D) v1.0 were collected at baseline and post-procedure short term (<3-months) and long-term (6-12 month) follow-up. Statistical analysis comparing baseline and postprocedural PROMIS scores was performed. Differences were compared with previously established minimal clinically important differences in the spine population.
    Results: For patients with spinal stenosis treated with TFSNRI, no statistically significant improvement was observed short- and long-term follow-up in PROMIS PF (P=.97, .77) and PROMIS Depression (P=.86, .85) scores. At short-term follow-up, PROMIS PI scores did significantly improve (P=.01) but the average difference of pre- and post-procedure scores did not reach clinical significance. No significant difference in PROMIS PI was noted at long-term follow-up (.75).
    Conclusions: Although a statistically significant difference was observed for improvement in pain, in this retrospective study, TFSNRI did not provide clinically significant improvement in patients' function, pain, or depression for lumbar spinal stenosis at short- and long-term follow-up.
    Language English
    Publishing date 2024-02-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80057-0
    ISSN 1532-821X ; 0003-9993
    ISSN (online) 1532-821X
    ISSN 0003-9993
    DOI 10.1016/j.apmr.2024.02.720
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