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Biomedical subjects

Michael Sussman

Publications and source records attributed to Michael Sussman.

7 recordsLinked to original sources
PubMed2026

Lipid transfer proteins and PI4KIIα generate a phosphoinositide-linked proteome.

Phosphoinositide (PIPn) lipid second messengers in membranes regulate numerous cellular processes. In the cytosol, the phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway is scaffolded on IQGAP1 to facilitate the activation of Akt by the synthesis of PI3,4,5P3. In the nucleus, PIPn signaling occurs in compartments separate from membranes by stably linking PIPns to nuclear proteins. While several of these proteins have been identified, understanding the extent and impact of protein-linked PIPn signaling warrants further investigation. The tumor suppressor p53, was shown in the companion paper to be regulated by PI transfer proteins (PITPs) and a PI 4-kinase (PI4KIIα), which are required to form p53-PIPn complexes that assemble a nuclear PI3K/Akt pathway. Here we report that class I PITPs (PITPα/β) and PI4KIIα initiate PIPn linkages to many different proteins. PITPα/β and PI4KIIα accumulate in the nucleoplasm in response to stress and are necessary to synthesize nuclear PIPns linked to proteins. These PITPα/β-dependent protein-PIPn complexes are detected by metabolically labeling cells with the PIPn precursor [3H]-myo-inositol and resist denaturation and SDS-PAGE, indicating that these protein-PIPn complexes represent a putative posttranslational modification. Proteomic and gene set enrichment analysis of proteins that are linked to PI4,5P2 reveals an emerging PIPn-linked proteome (PIPylome) regulated by PITPα/β and enriched in proteins that play key functional roles in metabolism, cell motility/division, and the DNA damage response. The PIPn-linked proteome represents a third messenger signaling paradigm distinct from the canonical membrane-localized pathway whereby linked PIPn messengers regulate protein function.

Phosphatidylinositols↗
PubMed2004

Gene targeting in stem cells from individuals with osteogenesis imperfecta.

Adult stem cells offer the potential to treat many diseases through a combination of ex vivo genetic manipulation and autologous transplantation. Mesenchymal stem cells (MSCs, also referred to as marrow stromal cells) are adult stem cells that can be isolated as proliferating, adherent cells from bones. MSCs can differentiate into multiple cell types present in several tissues, including bone, fat, cartilage, and muscle, making them ideal candidates for a variety of cell-based therapies. Here, we have used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 collagen genes in MSCs from individuals with the brittle bone disorder osteogenesis imperfecta, demonstrating successful gene targeting in adult human stem cells.

Alleles↗
PubMed2004

Comparison of three ankle-foot orthosis configurations for children with spastic diplegia.

This study compared the functional efficacy of three commonly prescribed ankle-foot orthosis (AFO) configurations (solid [SAFO], hinged [HAFO], and posterior leaf spring [PLS]). Sixteen independently ambulatory children (10 males, six females; mean age 8 years 4 months, SD 2 years 4 months; range 4 years 4 months to 11 years 6 months) with spastic diplegia participated in this study. Four children were classified at level I of the Gross Motor Function Classification System (GMFCS; Palisano et al. 1997); the remaining 12 were at level II. Children were assessed barefoot (BF) at baseline (baseline assessment of energy consumption was performed with shoes on, no AFO) and in each orthotic configuration after three months of use, using gait analysis, oxygen consumption, and functional outcome measures. AFO use did not markedly alter joint kinematics or kinetics at the pelvis, hip, or knee. All AFO configurations normalized ankle kinematics in stance, increased step/stride length, decreased cadence, and decreased energy cost of walking. Functionally, all AFO configurations improved the execution of walking/running/jumping skills, upper extremity coordination, and fine motor speed/dexterity. However, the quality of gross motor skill performance and independence in mobility were unchanged. These results suggest that most children with spastic diplegia benefit functionally from AFO use. However, some children at GMFCS level II demonstrated a subtle but detrimental effect on function with HAFO use, shown by an increase in peak knee extensor moment in early stance, excessive ankle dorsiflexion, decreased walking velocity, and greater energy cost. Therefore, constraining ankle motion by using a PLS or SAFO should be considered for most, but not all, children with spastic diplegia.

Ankle Joint↗
PubMed2003

Got silicon? The non-essential beneficial plant nutrient.

Research on a possible nutritional role for the element silicon has been hampered by the diverse beneficial effects that it has on monocots and dicots, and the subsequent difficulties in focusing studies on a single genetic model system. Although deemed a non-essential nutrient for the majority of plants, the benefits of silicon include increasing pest and pathogen resistance, drought and heavy metal tolerance, and the quality and yield of agricultural crops. Although the pathways and molecular mechanisms by which silicon is absorbed and deposited in plants are still unclear, recent progress has been achieved through the use of rice mutants that are deficient in silicon uptake. Additionally, the application of electron-energy-loss spectroscopy (EELS) allows one to determine the composition of silica deposits conclusively. Thereby shedding light upon the role of silicon in heavy metal tolerance. With the complete sequence of the genomes for a dicot (Arabidopsis) and a monocot (rice) available for large-scale genetic analysis, the future bodes well for a more complete understanding of the biological role of silicon and its mode of transport into and through plants.

Adaptation, Physiological↗
PubMedDate not supplied

Spinal deformity after selective dorsal rhizotomy in ambulatory patients with cerebral palsy.

Thirty-four patients with ambulatory spastic diplegia (ages 10-19.8 years) who were part of a prospective study of selective dorsal rhizotomy (SDR) had standardized radiographs before and after SDR. Follow-up ranged from 5 to 11.6 years after surgery. Two different surgical approaches were used: laminectomy (14 patients) and laminoplasty (20 patients). Radiographs were measured for coronal and sagittal balance. Thirty patients had a spinal deformity at long-term follow-up compared with 10 patients before surgery. Seventeen patients (50%) developed lumbar hyperlordosis greater than 60 degrees. Six patients (18%) developed grade 1 spondylolisthesis, Scoliosis occurred de novo in eight patients (24%) and progressed by greater than 5 degrees in two patients with preoperative scoliosis. No significant differences were found between laminoplasty and laminectomy patients. None of the patients have undergone any surgical intervention for spinal deformity. There was a higher incidence of spinal deformity after SDR than in normals and an historical control population, which warrants clinical and radiographic long-term follow-up.

Adolescent↗
PubMedDate not supplied

Recurrence after femoral derotational osteotomy in cerebral palsy.

The authors studied the long-term results of femoral derotational osteotomy (FDO) for medial femoral torsion in ambulatory children with cerebral palsy. Thirty children with 45 femurs that underwent distal FDO were followed for a mean of 6.5 years. Although correction was achieved after surgery, recurrence occurred during follow-up in 15 femurs. Preoperative mean external hip rotation of 10.7 +/- 7.2 degrees increased to 41.3 +/- 16.6 degrees 1 year after surgery and decreased to 28.2 +/- 14.7 degrees 5 years after surgery. On kinematic data, maximum hip rotation in stance of 30 degrees before surgery decreased to 8.7 degrees 1 year after surgery and increased to 16.1 degrees 5 years after surgery. Minimum hip rotation of 10.4 degrees before surgery was corrected to -4.3 degrees 1 year after surgery and was 0.8 degrees 5 years after surgery. Passive hip external rotation and kinematic hip rotation showed progressive deterioration of the initial correction. Patients having surgery prior to age 10 were more likely to show deterioration.

Cerebral Palsy↗
PubMedDate not supplied

Duchenne muscular dystrophy.

Duchenne muscular dystrophy is an X-linked disease of muscle caused by an absence of the protein dystrophin. Affected boys begin manifesting signs of disease early in life, cease walking at the beginning of the second decade, and usually die by age 20 years. Until treatment of the basic genetic defect is available, medical, surgical, and rehabilitative approaches can be used to maintain patient function and comfort. Corticosteroids, including prednisone and a related compound, deflazacort, have recently been shown to markedly delay the loss of muscle strength and function in boys with Duchenne muscular dystrophy. Surgical release of lower extremity contractures may benefit some patients. Approximately 90% of boys with Duchenne muscular dystrophy will develop severe scoliosis, which is not amenable to control by nonsurgical means such as bracing or adaptive seating. The most effective treatment for severe scoliosis is prevention by intervening with early spinal fusion utilizing segmental instrumentation as soon as curves are ascertained and before the onset of severe pulmonary or cardiac dysfunction.

Animals↗