Scanning tunneling spectroscopy was used to investigate single crystals and thin films of La 1– x... more Scanning tunneling spectroscopy was used to investigate single crystals and thin films of La 1– x Ca x MnO 3 (with x of about 0.3), which exhibit colossal magnetoresistance. The different spectroscopic signatures of the insulating (paramagnetic) and metallic (ferromagnetic) phases enable their spatial extent to be imaged down to a lateral scale of the order of 10 nanometers. Above the bulk transition temperature T c , the images show mostly insulating behavior. Below T c , a phase separation is observed where inhomogeneous structures of metallic and more insulating areas coexist and are strongly field dependent in their size and structure. Insulating areas are found to persist far below T c . These results suggest that the transition and the associated magnetoresistance behavior should be viewed as a percolation of metallic ferromagnetic domains.
bioRxiv (Cold Spring Harbor Laboratory), Jul 15, 2023
Many animals assume characteristic postures when resting or sleeping. These postures are often st... more Many animals assume characteristic postures when resting or sleeping. These postures are often stable and can be maintained passively, thus reducing the energy cost for maintaining an unstable posture. For example, many tetrapods lay prone on the ground and some negatively buoyant fishes are also able to rest on the substrate. Other fishes rest suspended in the water column. Counterintuitively, hovering this way can be of similar energetic cost to swimming. Even if the fish is perfectly neutrally buoyant, any displacement between its center of mass and center of buoyancy will produce destabilizing pitching torques that the fish must constantly work to counteract if they wish to maintain that posture. We hypothesized that a neutrally buoyant fish could rest at an equilibrium-a posture at which no destabilizing torques are produced by the body-to minimize the metabolic costs associated with hovering. Specifically, we studied the bluegill sunfish (Lepomis macrochirus), which is unstable in a horizontal posture. However, by pitching their bodies up or down they may be able to attain a less costly equilibrium posture, one which vertically aligns their center of mass and center of buoyancy. To test this hypothesis, we measured pitch angle of bluegill over the course of 24 hours. We also measured the pitch angles of the body that correspond to stable and unstable equilibria. We found that the stable equilibrium was a belly-up posture, and the unstable equilibrium is a dorsal side up posture pitched 53±26° head-down. The fish rested at a head-down pitch of-10.7±0.4° degrees, which is significantly steeper than the average pitch during the day of-3.4±0.8° degrees head down. These results show that bluegill do not rest at unstable or stable equilibrium. However, they do rest closer to unstable equilibrium at night than during the day. This may allow them to decrease destabilizing torques generated from the relative locations of the COM and COB while maintaining maneuverability. .
Static stability is a property inherent to every organism. More stable bodies benefit from a lowe... more Static stability is a property inherent to every organism. More stable bodies benefit from a lower energetic cost associated with maintaining a desired orientation, while less stable bodies can be more maneuverable. The static stability of a fish is determined by the relative locations of its center of mass and center of buoyancy, which may change with changes in swim bladder volume. We hypothesized, however, that fish would benefit from consistent static stability, and predicted that changes in swim bladder volume would not alter the overall pattern of COM and COB locations. We used microcomputed tomography to estimate the locations of the center of mass and center of buoyancy in bluegill sunfish (Lepomis macrochirus). Using this technique we were able to find a small but significant difference between the location of the COM and COB for a given orientation. We found that the swim bladder can change shape within the body cavity, changing relative locations of the COM and COB. At one extreme, the center of buoyancy is located 0.441 ± 0.007 BL from the snout and 0.190 ± 0.010 BL from the ventral surface of the pelvic girdle, and that the center of mass is 0.0030 ± 0.0020 BL posterior and 0.0006 ± 0.0005 BL ventral to the center of buoyancy, a pattern that causes a nose-up pitching torque. At the other extreme, the center of mass is anterior and dorsal to the center of buoyancy, a pattern that causes the opposite torque. These changes in location seems to be caused by changes in the shape and centroid location of the swim bladder within the body: the centroid of the swim bladder is located significantly more posteriorly in fish oriented head-down. The air in the bladder "rises" while heavier tissues "sink," driving a change in tissue distribution and changing the location of the center of mass relative to the center of buoyancy. Supporting our hypothesis, we found no correlation between swim bladder volume and the distance between the center of mass and center of buoyancy. We conclude that bluegill are statically unstable, requiring them to expend energy constantly to maintain their normal orientation, but that the pitch angle of the body could alter the relative locations of COM and COB, changing their static stability.
Colicin V (ColV) is peptide antibiotic secreted by Escherichia coli through a dedicated exporter ... more Colicin V (ColV) is peptide antibiotic secreted by Escherichia coli through a dedicated exporter composed of three proteins, CvaA, CvaB, and TolC. ColV secretion is independent of the E. coli general secretory pathway (Sec) but requires an N-terminal export signal specific for the CvaAB/TolC exporter. ColV secretion was characterized using genetic and biochemical methods. When the ColV N-terminal extension is replaced with the OmpA signal sequence, the Sec system can localize ColV to the periplasm. Periplasmic ColV is lethal to cells lacking the ColV immunity protein, Cvi. Based on this result, a genetic assay was designed to monitor for the presence of periplasmic ColV during normal CvaAB/TolC mediated secretion. Results indicate that low levels of ColV may be present in the periplasm during secretion. Precursor and mature ColV were also characterized from the wild-type system and in various exporter mutant backgrounds using immunoprecipitation. ColV processing is rapid in wild-typ...
A mini-Tn10-kan insertion mutation identified a gene in the chromosome of Escherichia coli requir... more A mini-Tn10-kan insertion mutation identified a gene in the chromosome of Escherichia coli required for colicin V production from plasmid pColV-K30. With the complete restriction map of E. coli, the mutation was rapidly mapped to 50.0 min, within the purF operon. Sequence analysis showed that the insertion occurred in a gene with no previously known function which is located directly upstream of purF. We designated this gene cvpA for colicin V production. The mutant requires adenine for growth, probably because of a polar effect on purF expression. However, an adenine auxotroph showed no defect in colicin V production, suggesting that the cvpA mutation is responsible for the effect on colicin V production. Two possible models of cvpA1 allele function are discussed.
The antibacterial protein Colicin V (ColV) is secreted from gram-negative bacteria by a signal se... more The antibacterial protein Colicin V (ColV) is secreted from gram-negative bacteria by a signal sequence-independent pathway. The proteins that mediate the export of ColV share sequence similarities with components from other signal sequence-independent export systems such as those for alpha-hemolysin (Hly) and Erwinia protease (Prt). We report here that the intact HlyBD export system can export active ColV from Escherichia coli strains lacking the ColV export proteins CvaA and CvaB. The individual Hly export genes complement mutations in their respective ColV homologs, but do so at a lower efficiency. When CvaA or CvaB is expressed along with the intact HlyBD exporter, the Cva export protein interferes with export of ColV through the HlyBD system. Gene fusions and point mutations in the ColV structural gene were used to define signals in ColV recognized by the Hly exporter. An export signal in ColV recognized by HlyBD is localized to the amino-terminal 57 amino acids of the protein....
Background: Lopinavir/ritonavir (LPV/r) single-agent therapy can achieve and sustain virologic su... more Background: Lopinavir/ritonavir (LPV/r) single-agent therapy can achieve and sustain virologic suppression in a variety of treatment strategies. Long-term data of the durability of LPV/r as (SAT) in naïve subjects remain limited. Methods: : IMANI-2 is a prospective, phase II, single-arm, open-label, 96-week pilot trial of LPV/r single-agent therapy in 39 ARV naïve subjects. Any VL and CD4 count without baseline resistance to LPV/r were eligible. Study endpoints at 48 weeks (VL <75 in 79% ITT M=F) have been reported previously. Final 96 week data on virologic and immunologic response are presented. Results: At week 96, 29/39 (74.3% ITT M=F) and 29/33 (87.8% AT ) subjects had VL <75 copies/ml. 4 were viremic (101, 217, 794, 24,778 copies). 6 D/C prior to 96 weeks, 1 due to protocol violation, and 5 LTFU. 5 intensified before 48 weeks. 4/5 <75 copies/ml by week 48, but were among the LTFU before week 96. 12 experienced transient viremia (7 multiple, 5 singular) after achieving...
B and T lymphocytes contact antigen at different stages of maturation and in a different cellular... more B and T lymphocytes contact antigen at different stages of maturation and in a different cellular context. Depending on these circumstances, their responses can be entirely different. Immature double-positive (CD4&amp;amp;amp;amp;amp;amp;quot;^/CD8^) thymocytes can be positively selected ...
This study evaluated the safety and efficacy of switching HIV-infected patients with stable viral... more This study evaluated the safety and efficacy of switching HIV-infected patients with stable viral suppression on nonnucleoside reverse transcriptase inhibitor/nucleoside reverse transcriptase inhibitor (NNRTI/NRTI) therapy to lopinavir/ritonavir (LPV/r) monotherapy. Eligible patients discontinued NNRTI and started LPV/r. Two weeks later NRTIs were stopped and LPV/r monotherapy was continued. Patients were seen every 4 weeks throughout the 48-week study. Twelve of 18 (66%) participants met the primary endpoint with HIV RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 copies/mL at week 48. Thirteen (72%) participants completed 48 weeks of LPV/r monotherapy, and 12 of 13 (92%) participants on treatment at week 48 had HIV RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 copies/mL. Ten (55%) of 18 patients maintained HIV RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 copies/mL at all time points. Two patients were withdrawn with virologic failure but demonstrated no evidence of virologic resistance. Three (17%) patients withdrew due to diarrhea, 2 with hyperglycemia at baseline developed diabetes mellitus, 7 (54%) required addition of or increase in lipid-lowering agents, but none had grade 3 or 4 hyperlipidemia. Results from this pilot study suggest that LPV/r monotherapy may be an option for management of HIV infection. Larger, randomized trials are warranted to evaluate the safety, efficacy, and patient population who might benefit from LPV/r monotherapy.
Scanning tunneling spectroscopy was used to investigate single crystals and thin films of La 1– x... more Scanning tunneling spectroscopy was used to investigate single crystals and thin films of La 1– x Ca x MnO 3 (with x of about 0.3), which exhibit colossal magnetoresistance. The different spectroscopic signatures of the insulating (paramagnetic) and metallic (ferromagnetic) phases enable their spatial extent to be imaged down to a lateral scale of the order of 10 nanometers. Above the bulk transition temperature T c , the images show mostly insulating behavior. Below T c , a phase separation is observed where inhomogeneous structures of metallic and more insulating areas coexist and are strongly field dependent in their size and structure. Insulating areas are found to persist far below T c . These results suggest that the transition and the associated magnetoresistance behavior should be viewed as a percolation of metallic ferromagnetic domains.
bioRxiv (Cold Spring Harbor Laboratory), Jul 15, 2023
Many animals assume characteristic postures when resting or sleeping. These postures are often st... more Many animals assume characteristic postures when resting or sleeping. These postures are often stable and can be maintained passively, thus reducing the energy cost for maintaining an unstable posture. For example, many tetrapods lay prone on the ground and some negatively buoyant fishes are also able to rest on the substrate. Other fishes rest suspended in the water column. Counterintuitively, hovering this way can be of similar energetic cost to swimming. Even if the fish is perfectly neutrally buoyant, any displacement between its center of mass and center of buoyancy will produce destabilizing pitching torques that the fish must constantly work to counteract if they wish to maintain that posture. We hypothesized that a neutrally buoyant fish could rest at an equilibrium-a posture at which no destabilizing torques are produced by the body-to minimize the metabolic costs associated with hovering. Specifically, we studied the bluegill sunfish (Lepomis macrochirus), which is unstable in a horizontal posture. However, by pitching their bodies up or down they may be able to attain a less costly equilibrium posture, one which vertically aligns their center of mass and center of buoyancy. To test this hypothesis, we measured pitch angle of bluegill over the course of 24 hours. We also measured the pitch angles of the body that correspond to stable and unstable equilibria. We found that the stable equilibrium was a belly-up posture, and the unstable equilibrium is a dorsal side up posture pitched 53±26° head-down. The fish rested at a head-down pitch of-10.7±0.4° degrees, which is significantly steeper than the average pitch during the day of-3.4±0.8° degrees head down. These results show that bluegill do not rest at unstable or stable equilibrium. However, they do rest closer to unstable equilibrium at night than during the day. This may allow them to decrease destabilizing torques generated from the relative locations of the COM and COB while maintaining maneuverability. .
Static stability is a property inherent to every organism. More stable bodies benefit from a lowe... more Static stability is a property inherent to every organism. More stable bodies benefit from a lower energetic cost associated with maintaining a desired orientation, while less stable bodies can be more maneuverable. The static stability of a fish is determined by the relative locations of its center of mass and center of buoyancy, which may change with changes in swim bladder volume. We hypothesized, however, that fish would benefit from consistent static stability, and predicted that changes in swim bladder volume would not alter the overall pattern of COM and COB locations. We used microcomputed tomography to estimate the locations of the center of mass and center of buoyancy in bluegill sunfish (Lepomis macrochirus). Using this technique we were able to find a small but significant difference between the location of the COM and COB for a given orientation. We found that the swim bladder can change shape within the body cavity, changing relative locations of the COM and COB. At one extreme, the center of buoyancy is located 0.441 ± 0.007 BL from the snout and 0.190 ± 0.010 BL from the ventral surface of the pelvic girdle, and that the center of mass is 0.0030 ± 0.0020 BL posterior and 0.0006 ± 0.0005 BL ventral to the center of buoyancy, a pattern that causes a nose-up pitching torque. At the other extreme, the center of mass is anterior and dorsal to the center of buoyancy, a pattern that causes the opposite torque. These changes in location seems to be caused by changes in the shape and centroid location of the swim bladder within the body: the centroid of the swim bladder is located significantly more posteriorly in fish oriented head-down. The air in the bladder "rises" while heavier tissues "sink," driving a change in tissue distribution and changing the location of the center of mass relative to the center of buoyancy. Supporting our hypothesis, we found no correlation between swim bladder volume and the distance between the center of mass and center of buoyancy. We conclude that bluegill are statically unstable, requiring them to expend energy constantly to maintain their normal orientation, but that the pitch angle of the body could alter the relative locations of COM and COB, changing their static stability.
Colicin V (ColV) is peptide antibiotic secreted by Escherichia coli through a dedicated exporter ... more Colicin V (ColV) is peptide antibiotic secreted by Escherichia coli through a dedicated exporter composed of three proteins, CvaA, CvaB, and TolC. ColV secretion is independent of the E. coli general secretory pathway (Sec) but requires an N-terminal export signal specific for the CvaAB/TolC exporter. ColV secretion was characterized using genetic and biochemical methods. When the ColV N-terminal extension is replaced with the OmpA signal sequence, the Sec system can localize ColV to the periplasm. Periplasmic ColV is lethal to cells lacking the ColV immunity protein, Cvi. Based on this result, a genetic assay was designed to monitor for the presence of periplasmic ColV during normal CvaAB/TolC mediated secretion. Results indicate that low levels of ColV may be present in the periplasm during secretion. Precursor and mature ColV were also characterized from the wild-type system and in various exporter mutant backgrounds using immunoprecipitation. ColV processing is rapid in wild-typ...
A mini-Tn10-kan insertion mutation identified a gene in the chromosome of Escherichia coli requir... more A mini-Tn10-kan insertion mutation identified a gene in the chromosome of Escherichia coli required for colicin V production from plasmid pColV-K30. With the complete restriction map of E. coli, the mutation was rapidly mapped to 50.0 min, within the purF operon. Sequence analysis showed that the insertion occurred in a gene with no previously known function which is located directly upstream of purF. We designated this gene cvpA for colicin V production. The mutant requires adenine for growth, probably because of a polar effect on purF expression. However, an adenine auxotroph showed no defect in colicin V production, suggesting that the cvpA mutation is responsible for the effect on colicin V production. Two possible models of cvpA1 allele function are discussed.
The antibacterial protein Colicin V (ColV) is secreted from gram-negative bacteria by a signal se... more The antibacterial protein Colicin V (ColV) is secreted from gram-negative bacteria by a signal sequence-independent pathway. The proteins that mediate the export of ColV share sequence similarities with components from other signal sequence-independent export systems such as those for alpha-hemolysin (Hly) and Erwinia protease (Prt). We report here that the intact HlyBD export system can export active ColV from Escherichia coli strains lacking the ColV export proteins CvaA and CvaB. The individual Hly export genes complement mutations in their respective ColV homologs, but do so at a lower efficiency. When CvaA or CvaB is expressed along with the intact HlyBD exporter, the Cva export protein interferes with export of ColV through the HlyBD system. Gene fusions and point mutations in the ColV structural gene were used to define signals in ColV recognized by the Hly exporter. An export signal in ColV recognized by HlyBD is localized to the amino-terminal 57 amino acids of the protein....
Background: Lopinavir/ritonavir (LPV/r) single-agent therapy can achieve and sustain virologic su... more Background: Lopinavir/ritonavir (LPV/r) single-agent therapy can achieve and sustain virologic suppression in a variety of treatment strategies. Long-term data of the durability of LPV/r as (SAT) in naïve subjects remain limited. Methods: : IMANI-2 is a prospective, phase II, single-arm, open-label, 96-week pilot trial of LPV/r single-agent therapy in 39 ARV naïve subjects. Any VL and CD4 count without baseline resistance to LPV/r were eligible. Study endpoints at 48 weeks (VL <75 in 79% ITT M=F) have been reported previously. Final 96 week data on virologic and immunologic response are presented. Results: At week 96, 29/39 (74.3% ITT M=F) and 29/33 (87.8% AT ) subjects had VL <75 copies/ml. 4 were viremic (101, 217, 794, 24,778 copies). 6 D/C prior to 96 weeks, 1 due to protocol violation, and 5 LTFU. 5 intensified before 48 weeks. 4/5 <75 copies/ml by week 48, but were among the LTFU before week 96. 12 experienced transient viremia (7 multiple, 5 singular) after achieving...
B and T lymphocytes contact antigen at different stages of maturation and in a different cellular... more B and T lymphocytes contact antigen at different stages of maturation and in a different cellular context. Depending on these circumstances, their responses can be entirely different. Immature double-positive (CD4&amp;amp;amp;amp;amp;amp;quot;^/CD8^) thymocytes can be positively selected ...
This study evaluated the safety and efficacy of switching HIV-infected patients with stable viral... more This study evaluated the safety and efficacy of switching HIV-infected patients with stable viral suppression on nonnucleoside reverse transcriptase inhibitor/nucleoside reverse transcriptase inhibitor (NNRTI/NRTI) therapy to lopinavir/ritonavir (LPV/r) monotherapy. Eligible patients discontinued NNRTI and started LPV/r. Two weeks later NRTIs were stopped and LPV/r monotherapy was continued. Patients were seen every 4 weeks throughout the 48-week study. Twelve of 18 (66%) participants met the primary endpoint with HIV RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 copies/mL at week 48. Thirteen (72%) participants completed 48 weeks of LPV/r monotherapy, and 12 of 13 (92%) participants on treatment at week 48 had HIV RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 copies/mL. Ten (55%) of 18 patients maintained HIV RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 copies/mL at all time points. Two patients were withdrawn with virologic failure but demonstrated no evidence of virologic resistance. Three (17%) patients withdrew due to diarrhea, 2 with hyperglycemia at baseline developed diabetes mellitus, 7 (54%) required addition of or increase in lipid-lowering agents, but none had grade 3 or 4 hyperlipidemia. Results from this pilot study suggest that LPV/r monotherapy may be an option for management of HIV infection. Larger, randomized trials are warranted to evaluate the safety, efficacy, and patient population who might benefit from LPV/r monotherapy.
Uploads
Papers by Mike Fath