A5041139810- Nuclear Structure and Function
- Cellular Mechanics and Interactions
- RNA Research and Splicing
- Bacteriophages and microbial interactions
- Skin and Cellular Biology Research
- Genomics and Chromatin Dynamics
- Microtubule and mitosis dynamics
- Lipid metabolism and biosynthesis
- DNA Repair Mechanisms
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- MicroRNA in disease regulation
- Plant Virus Research Studies
- Cancer-related molecular mechanisms research
- Virus-based gene therapy research
- Collagen: Extraction and Characterization
- 3D Printing in Biomedical Research
- Bacterial Genetics and Biotechnology
- Force Microscopy Techniques and Applications
- Retinoids in leukemia and cellular processes
- Viral gastroenteritis research and epidemiology
- Mesenchymal stem cell research
- Circular RNAs in diseases
- Bone Tissue Engineering Materials
- Fungal and yeast genetics research
University of Pennsylvania
2014-2024
Celdara Medical (United States)
2022
Philadelphia University
2019-2020
Physical Sciences (United States)
2016-2019
Merck & Co., Inc., Rahway, NJ, USA (United States)
2011-2017
Vrije Universiteit Amsterdam
2004-2012
Rosetta Stone (United States)
2008-2011
Leiden University
2009
Merck (Japan)
2009
Johns Hopkins Medicine
2006
Tissues can be soft like fat, which bears little stress, or stiff bone, sustains high but whether there is a systematic relationship between tissue mechanics and differentiation unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with elasticity, E, as did collagens in extracellular matrix determine E. Stem cell into fat on was enhanced by low levels, whereas bone levels. Matrix stiffness directly influenced and, although transcription...
Cell migration through solid tissue often involves large contortions of the nucleus, but biological significance is largely unclear. The nucleoskeletal protein lamin-A varies both within and between cell types was shown here to contribute sorting survival in constraining micropores. Lamin-A proved rate-limiting 3D diverse human cells that ranged from glioma adenocarcinoma lines primary mesenchymal stem (MSCs). Stoichiometry A- B-type lamins established an activation barrier, with high...
AbstractmicroRNAs in the miR-106b family are overexpressed multiple tumor types and correlated with expression of genes that regulate cell cycle. Consistent these observations, gain function promotes cycle progression, whereas loss reverses this phenotype. Microarray profiling uncovers targets family, including cyclin-dependent kinase inhibitor p21/CDKN1A. We show p21 is a direct target its silencing plays key role miR-106b-induced phenotypes. also overrides doxorubicin-induced DNA damage...
Cellular organization within a multicellular organism requires that cell assess its relative location, taking in multiple cues from microenvironment. Given the extracellular matrix (ECM) consists of most abundant proteins animals and contributes both structure elasticity to tissues, ECM probably provides key physical cells. In vivo, vicinity many tissue types, fibrous characteristics are less discernible than measurably distinct characterizes different microenvironments. As engages actively...
The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix-all of which sustain forces, but their relationships DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization multiple repair factors correlates high curvature imposed by an external probe or cell attachment either aligned collagen fibers stiff matrix. Mislocalization greatly enhanced lamin A depletion, requires hours for reentry, increase in pan-nucleoplasmic foci marker...
The shell of bacteriophages protects the viral DNA during host-to-host transfer and serves as a high-pressure container storing energy for injection into host bacterium. Here, we probe mechanical properties nanometer-sized bacteriophage φ29 shells by applying point forces. We show that empty withstand nanonewton forces while being indented up to 30% their height. elastic response varies across surface, reflecting arrangement proteins. measured Young's modulus (≈1.8 GPa) is comparable with...
The elastic properties of capsids the cowpea chlorotic mottle virus have been examined at pH 4.8 by nanoindentation measurements with an atomic force microscope. Studies carried out on WT capsids, both empty and containing RNA genome, full a salt-stable mutant subE mutant. Full resisted indentation more than but all were highly elastic. There was initial reversible linear regime that persisted up to indentations varying between 20% 30% diameter applied forces 0.6-1.0 nN; it followed steep...
Cell migration through solid tissue often involves large contortions of the nucleus, but biological significance is largely unclear. The nucleoskeletal protein lamin-A varies both within and between cell types was shown here to contribute sorting survival in constraining micropores. Lamin-A proved rate-limiting 3D-migration diverse human cells that ranged from glioma adenocarcinoma lines primary mesenchymal stem (MSCs). Stoichiometry A- B-type lamins established an activation barrier, with...
RNA interference-mediated suppression of DICER and DROSHA in human embryonic stem cells (hESCs) attenuates cell proliferation, supporting a role for an intact microRNA (miRNA) pathway the control hESC division. Normal growth can be partially restored by introduction mature miRNAs miR-195 miR-372. These regulate two tumor suppressor genes, respectively: WEE1, which encodes negative G2/M kinase modulator cycB/CDK complex CDKN1A, p21, cycE/CDK cyclin dependent inhibitor that regulates G1/S...
Studies of embryonic stem cells (ESCs) reveal that these cell lines can be derived from differing stages development. We analyzed common changes in the expression microRNAs (miRNAs) and mRNAs 9 different human ESC (hESC) during early commitment further examined key ESCenriched miRNAs earlier developmental states several species. show previously defined hESC-enriched miRNA groups (the miR-302, -17, -515 families, miR-371-373 cluster) other are down-regulated rapidly response to...
Hepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of malignant stemlike subtype HCC may offer patients with dismal prognosis potential targeted therapy using c-MET Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic prognostic tools cancer detection stratification. Using TRE-c-Met-driven transgenic mouse model, we identified cluster 23 miRNAs that encoded within the Dlk1-Gtl2 imprinted...
As a cell squeezes its nucleus through adjacent tissue, penetrates basement membrane, or enters small blood capillary, chromatin density and nuclear factors could in principle be physically perturbed. Here, cancer migration rigid micropores passive pulling into micropipettes, local compaction of is observed coincident with depletion mobile factors. Heterochromatin/euchromatin was previously estimated from molecular mobility measurements to occupy volume fraction f roughly two-thirds the...
Migration through 3D constrictions can cause nuclear rupture and mislocalization of proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues partially the marker γH2AX, an apparent block in cycle appears unaffected. Co-overexpression multiple repair factors or antioxidant break formation also exert partial effects, independently rupture. Combined treatments completely rescue suppression by damage, revealing a sigmoidal dependence...
KAR1 is required for duplication of the Saccharomyces cerevisiae microtubule organizing center, spindle pole body (SPB) (Rose, M.D., and G.R. Fink, 1987. Cell. 48:1047-1060). Suppressors a kar1 allele defective SPB were isolated in two genes, CDC31 DSK2 (Vallen, E.A., W.H., M. Winey, M.D. Rose. 1994. Genetics. 137:407-422). To elucidate role duplication, we cloned gene found it encodes novel ubiquitin-like protein containing an NH2 terminus 36% identical to ubiquitin. The only other known...
We report a combined theoretical and experimental study of the structural failure viral shells under mechanical stress. find that discontinuities in force-indentation curve associated with should appear when so-called Föppl-von Kármán (FvK) number exceeds critical value. A nanoindentation shell subject to soft-mode instability, where stiffness decreases increasing pH, confirms predicted onset as function FvK number.
dsDNA in bacteriophages is highly stressed and exerts internal pressures of many atmospheres (1 atm = 101.3 kPa) on the capsid walls. We investigate correlation between packaged DNA length lambda phage (78-100% WT DNA) strength by using an atomic force microscope indentation technique. show that phages with are twice as strong shorter genome mutants, which behave like empty capsids, regardless high pressure. Our analytical model DNA-filled deformation shows that, because DNA-hydrating water...
Synergistic cues from extracellular matrix and soluble factors are often obscure in differentiation. Here the rigidity of cross-linked collagen synergizes with retinoids osteogenesis human marrow mesenchymal stem cells (MSCs). Collagen nanofilms serve as a model that MSCs can easily deform unless film is enzymatically cross-linked, which promotes spreading stiffening nuclei both actomyosin assembly nucleoskeletal lamin-A increase. Expression known to be controlled by retinoic acid receptor...
The nucleus in many cell types is a stiff organelle, but fat-filled lipid droplets (FDs) cytoplasm are seen to indent and displace the nucleus. FDs phase-separated liquids with poorly understood interfacial tension γ that determines how interact other organelles. Here, micron-sized remain spherical as they peri-nuclear actomyosin nucleus, while causing local dilution of Lamin-B1 independent Lamin-A,C sometimes triggering nuclear rupture. Focal accumulation cytosolic DNA sensor cGAS at...
To promote faithful propagation of the genetic material during sexual reproduction, meiotic chromosomes undergo specialized morphological changes that ensure accurate segregation homologous chromosomes. The molecular mechanisms establish chromosomal structures are largely unknown. We describe a mutation in recently identified Histone H2A kinase, nhk-1 , Drosophila leads to female sterility due defects formation structures. metaphase I arrest and karyosome, critical prophase structure,...