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PubMed2025

SHICEDO: single-cell Hi-C data enhancement with reduced over-smoothing.

MOTIVATION: Single-cell Hi-C (scHi-C) technologies have significantly advanced our understanding of the 3D genome organization. However, scHi-C data are often sparse and noisy, leading to substantial computational challenges in downstream analyses. RESULTS: In this study, we introduce SHICEDO, a novel deep-learning model specifically designed to enhance scHi-C contact matrices by imputing missing or sparsely captured chromatin contacts through a generative adversarial framework. SHICEDO leverages the unique structural characteristics of scHi-C matrices to derive customized features that enable effective data enhancement. Additionally, the model incorporates a channel-wise attention mechanism to mitigate the over-smoothing issue commonly associated with scHi-C enhancement methods. Through simulations and real-data applications, we demonstrate that SHICEDO outperforms the state-of-the-art methods, achieving superior quantitative and qualitative results. Moreover, SHICEDO enhances key structural features in scHi-C data, thus enabling more precise delineation of chromatin structures such as A/B compartments, TAD-like domains, and chromatin loops. AVAILABILITY AND IMPLEMENTATION: SHICEDO is publicly available at https://github.com/wmalab/SHICEDO.

Single-Cell Analysis↗
PubMed2002

Bioengineering methods employed in the study of wound healing of sulphur mustard burns.

BACKGROUND/PURPOSE: Sulphur mustard (SM) is a potent incapacitating chemical warfare agent that remains a threat to war fighters and civilians worldwide. SM lesions may require weeks or months to heal, depending upon their severity. This study was undertaken to find a treatment regimen that promotes speedier healing of deep cutaneous SM burns in a weanling pig model. The principal objective of the study was to compare four treatment regimens and establish which achieved the shortest healing time. METHODS: Twelve Yorkshire Cross weanling pigs were exposed to SM liquid for 2h, generating six large deep dermal/full thickness burns on the ventrum of each animal. Three additional animals served as sham-exposed controls. Surgical intervention occurred at 48 h postexposure. Treatments included: (i) full-thickness debridement of the burns with a computer controlled, raster scanned continuous wave CO2 laser followed by autologous split-thickness skin grafting; (ii) full-thickness sharp surgical tangential excision followed by skin grafting, the 'Gold Standard' used in human deep dermal/full-thickness thermal burns management; (iii) partial-thickness laser ablation with no grafting; and (iv) partial-thickness sharp surgical excision with no grafting. Several non-invasive bioengineering methods were used to monitor the progress of wound healing throughout a 36-day healing period: reflectance colourimetry, evaporimetry, laser Doppler perfusion imaging and ballistometry. RESULTS: Bioengineering methods indicated that laser debridement followed by autologous split-thickness skin grafting was as efficacious in improving the wound healing of deep SM burns in weanling swine as the 'Gold Standard.' Regardless of the method of debridement, barrier function, skin colour and mechanical properties returned to near-normal levels within 15 days of treatment in the grafted sites. Regardless of surgical approach, blood flux levels remained approximately 50-60% of normal tissue throughout the 36-day postsurgical observation period. Mid-dermal debridement by sharp surgical tangential excision or laser ablation without the use of skin grafts did not produce as good a result as those attained through the use of grafts, but was better than no surgical treatment of the wounds. CONCLUSION: Bioengineering methods were useful in evaluating multiple characteristics during wound healing: (i) reflectance colourimetry for skin colour, (ii) evaporimetry to measure transepidermal water loss as an indicator of barrier function, (iii) laser Doppler perfusion imaging to assess cutaneous blood flow, and (iv) ballistometry to measure the mechanical properties of skin hardness and elasticity. Perhaps the most useful method was evaporimetry, as a restored barrier function was the best indicator of healed wounds. The use of reflectance colourimetry and ballistometry will continue in future wound healing studies for their contributions in judging cosmetic and functional outcomes. While useful, laser Doppler perfusion imaging was found to be rather time consuming. This methodology will be limited in the future to burn depth estimation prior to treatment, and for evaluation of pharmaceuticals specifically designed to improve or sustain blood flow into damaged areas.

Animals↗
PubMed2001

Deep brain stimulation for chronic pain: results of two multicenter trials and a structured review.

OBJECTIVES: A U.S. Food and Drug Administration ruling required clinical trials to evaluate the safety and efficacy of deep brain stimulation devices, thereby limiting treatment to the investigational setting. INTRODUCTION: As an investigator in two clinical trials of deep brain stimulation, I sought to determine why pain remained an unapproved indication despite regulatory approval of the same device for tremor. METHODS: The results of two multicenter trials of deep brain stimulation for pain were analyzed, and the pertinent literature was reviewed using published guidelines for the evaluation of clinical trial reports. RESULTS: The first-generation Model 3380 lead trial enrolled 196 patients; the current Model 3387 trial enrolled 50 patients. Prospectively defined criteria for success included at least half of patients reporting >/=50% pain relief at 1 year. Manufacture of the Model 3380 lead was discontinued, and the 3387 trial closed early because of slow enrollment, high attrition, and low efficacy. When results were analyzed according to the study plan, neither trial was successful. Consequently, deep brain stimulation has not been approved for pain control by the U.S. Food and Drug Administration. CONCLUSIONS: Deep brain stimulation has not been shown to produce effective long-term pain relief. Future studies of motor cortex stimulation and similar therapies will require appropriate control groups and accepted methods of data collection and analysis to support claims that predictable and reliable analgesic effects are produced in humans.

Journal Article↗
PubMed2004

Deep entry of defibrillating effects into homogeneous cardiac tissue.

A simple, idealized mathematical model of cardiac tissue is used to show that electrical fields applied with the intent of defibrillating the heart can be effective deep within (that is, many space constants into) cardiac tissue, even in cases when the tissue is assumed to have completely homogeneous electrical properties. This conclusion is drawn from the analysis of the two eigenmodes present in the model, which have fundamentally different characteristics. One mode decays very rapidly with space, implying that the associated membrane potential is only present with appreciable amplitude within a few space constants of the tissue surface. The other mode, however, is not directly dependent on the value of the space constant, and allows deep penetration of the membrane potential and, by implication, its associated defibrillating effects. For deep membrane potentials to be generated by this mechanism, the intracellular and extracellular resistivity anisotropy ratios must be unequal, as is typically the case in cardiac tissue. The model also predicts that this mechanism is most effective for a given applied field strength when the electrode size and separation, or spatial features of the externally applied field at the heart surface, are characterized by scalelengths that are commensurate with approximately two times the heart wall thickness.

Action Potentials↗
PubMed2004

Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity.

Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 microM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats.

Administration, Oral↗
PubMed2004

Deep hypothermia during ischemia improves functional recovery and reduces free-radical generation in isolated reperfused rat heart.

BACKGROUND: We investigated the influence of deep hypothermia (4 degrees C) during ischemia-reperfusion in the isolated rat heart model. METHODS: Isolated, perfused rat hearts underwent either 30 minutes of normothermic ischemia (control group) or 30 minutes of hypothermic ischemia (hypothermia-treated group), followed by 30 minutes of reperfusion in both groups. We recorded functional parameters and used electron spin resonance (ESR) spectroscopy to detect ascorbyl radicals, as markers of free-radical production, in samples of coronary effluents. RESULTS: Functional parameters were stable in the 2 groups during pre-ischemic and ischemic periods. During reperfusion, coronary flow, left diastolic ventricular pressure, left ventricular developed pressure, and heart rate more rapidly recovered to values close to those obtained during the pre-ischemic period in the hypothermia-treated group than in the control group. Moreover, the post-ischemic contracture observed in the control group did not appear in the hypothermia-treated group. Finally, ESR analysis showed that the post-ischemic release of ascorbyl radicals decreased in the hypothermia-treated group. CONCLUSIONS: These results demonstrate that the protective effect of hypothermia against functional injury caused by ischemia-reperfusion may decrease the free-radical burst at reperfusion.

Animals↗
PubMedDate not supplied

A deep model of the incidence of dental caries on proximal surfaces.

As a component of an analysis of the benefits of alternative frequencies of bitewing radiographs to detect dental caries, the authors developed and validated a model to generate an individual's probability distribution for new carious lesions in a year. The model postulates two sources of variability in caries incidence--differences in individuals' underlying caries susceptibilities and a random component. The model is used to examine the nature of caries risk over time. The large random fluctuations in an individual's caries susceptibility from year to year, combined with the random nature of caries attack, makes it difficult to predict future caries experience from the individual's caries experience in the recent past. By modeling the process giving rise to observed incidence data rather than focusing directly on the observed data, i.e., by developing a deep rather than a surface model, the authors have elucidated underlying disease dynamics and provided a basis for generalizing from the particular data used to develop the model.

Adolescent↗
PubMed2003

Measurement and prediction of ultralow frequency ocean ambient noise off the eastern U.S. coast.

Ultralow frequency (0.02-2 Hz) acoustic ambient noise was monitored from January to April 1991 at six ocean bottom stations off the eastern U.S. coast. The depths of the stations ranged from about 100 m to 2500 m. The measured spectra are in good agreement with predictions made using Cato's theory [J. Acoust. Soc. Am. 89, 1076-1095 (1991)] for noise generation by surface-wave orbital motion after extending the calculations to incorporate horizontally stratified environments. Contributions from both the linear, single-frequency (virtual monopole) and the nonlinear, double-frequency (dipole) mechanisms are clearly recognizable in the data. The predictions make use of directional wave data obtained from surface buoys deployed during the SWADE experiment and an ocean bottom model derived from compressional wave speed data measured during the EDGE deep seismic reflection survey. The results demonstrate conclusively that nonlinear surface-wave interactions are the dominant mechanism for generating deep-ocean ULF noise in the band 0.2-0.7 Hz.

Journal Article↗
PubMed2003

Wound fluid bacterial levels exceed tissue bacterial counts in controlled porcine partial-thickness burn infections.

In the present study, an established controlled burn wound model was used to test the hypothesis that controlled surface contamination with is capable of generating a noninvasive method for the creation of a reproducible deep tissue burn wound infection. Using a liquid tight-wound chamber in Yorkshire pigs, partial-thickness burns were inoculated with saline-immersed for 24 hours. Noninoculated burns and unwounded skin immersed in normal saline served as controls. Bacterial cultures of wound fluid were performed daily, and tissue biopsies for bacteriological and histological evaluations were performed on days 1, 3, and 5. was only recovered from -inoculated wounds (tissue and fluid), whereas all controls contained endogenous only. The number of colony-forming units per gram of wound tissue did not correlate with the bacterial counts found in the overlying wound fluid for any wounds. Fluid counts were consistently higher than tissue counts by two logs. -inoculated wounds showed three times deeper tissue destruction than control wounds. Obtaining consistently deep tissue colonization without cross-contamination among wounds, this study introduces a noninvasive model for controlled burn wound infection suitable for future investigations regarding the efficacy of topical antibiotic wound treatment in experimental burns.

Animals↗
PubMed2005

Simulation of equatorial and high-latitude jets on Jupiter in a deep convection model.

The bands of Jupiter represent a global system of powerful winds. Broad eastward equatorial jets are flanked by smaller-scale, higher-latitude jets flowing in alternating directions. Jupiter's large thermal emission suggests that the winds are powered from within, but the zonal flow depth is limited by increasing density and electrical conductivity in the molecular hydrogen-helium atmosphere towards the centre of the planet. Two types of planetary flow models have been explored: shallow-layer models reproduce multiple high-latitude jets, but not the equatorial flow system, and deep convection models only reproduce an eastward equatorial jet with two flanking neighbours. Here we present a numerical model of three-dimensional rotating convection in a relatively thin spherical shell that generates both types of jets. The simulated flow is turbulent and quasi-two-dimensional and, as observed for the jovian jets, simulated jet widths follow Rhines' scaling theory. Our findings imply that Jupiter's latitudinal transition in jet width corresponds to a separation between the bottom-bounded flow structures in higher latitudes and the deep equatorial flows.

Journal Article↗
PubMed2002

Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes.

B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations and has been associated with autoimmune disease. BAFF is known to interact with three receptors, BCMA, TACI and BAFF-R, that have distant similarities with other receptors of the TNF family. We have determined the crystal structure of the TNF-homologous domain of BAFF at 2.8 A resolution. The structure reveals significant differences when compared to other TNF family members, including an unusually long D-E loop that participates in the formation of a deep, concave and negatively charged region in the putative receptor binding site. The BAFF structure was further used to generate a homology model of APRIL, a closely related TNF family ligand that also binds to BCMA and TACI, but not BAFF-R. Analysis of the putative receptor binding sites of BAFF and APRIL suggests that differences in the D-E loop structure and electrostatic surface potentials may be important for determining binding specificities for BCMA, TACI and BAFF-R.

Amino Acid Sequence↗
PubMed2006

Electroconvulsive therapy stimulus dose expressed as volume of seizure foci.

BACKGROUND: Electrical stimulus dose is typically stated as charge in millicoulombs (mC), representing the number of electrons. However, by overlooking the voltage threshold for neuronal depolarization, charge alone is inappropriate. Any charge can accumulate from subthreshold voltage over time. Stimulus energy represents heat content; without a delivery rate, it is not related to depolarization voltage. The objective was to formulate stimulus dose in accordance with seizure induction physiology. METHOD: Stimulus dose was expressed as volume of generated seizure foci, a variable dependent on current and charge. A second more detailed model considers brain voltages as related to clinical deep brain stimulation. RESULTS: For the constant current stimuli characteristic of widely available American stimulators, stimulus dose is proportional to current cubed multiplied by charge. This relationship corresponds to the 3 dimensions of a voltage field in space, where the volume above a certain voltage increases with the cube of the voltage radius. As a consequence, any particular charge at 0.9 A (ampere) current has a seizure foci dose approximately 50% higher than the same charge at 0.8 A. CONCLUSIONS: The modeling offers an explanation for published measurements comparing instruments of maximum current 0.8 and 0.9 A. The modeling also suggests compensation approaches to be applied to the age-based bilateral stimulus dosing method. An electrical dosing strategy based on "half-age" (2.5 mC/y) is reasonable for 0.9-A stimulation but a "three-quarters age" (3.7 mC/y) is more appropriate for 0.8-A stimulation. The present results can allow doses and seizure thresholds to be compared between different currents, as when substituting one electroconvulsive therapy instrument for another.

Electroconvulsive Therapy↗
PubMed1996

Penetrative Convection and Zonal Flow on Jupiter

Measurements by the Galileo probe support the possibility that the zonal winds in Jupiter's atmosphere originate from convection that takes place in the deep hydrogen-helium interior. However, according to models based on recent opacity data and the probe's temperature measurements, there may be radiative and nonconvective layers in the outer part of the jovian interior, raising the question of how deep convection could extend to the surface. A theoretical model is presented to demonstrate that, because of predominant rotational effects and spherical geometry, thermal convection in the deep jovian interior can penetrate into any outer nonconvective layer. These penetrative convection rolls interact nonlinearly and efficiently in the model to generate and sustain a mean zonal wind with a larger amplitude than that of the nonaxisymmetric penetrative convective motions, a characteristic of the wind field observed at the cloud level on Jupiter.

Journal Article↗
PubMedDate not supplied

Prevention of postoperative mediastinitis: a clinical process improvement model.

In a prospective study of more than 4,000 consecutive patients who underwent any cardiovascular procedure requiring sternotomy incision in a 650-bed tertiary care hospital, a gradual increase in deep sternal infections from 0.8% in 1995 to 2.1% in 1999 was noted. By using a Plan-Do-Check-Act process improvement model, several interventions to decrease the infection rate were planned and implemented based on hypotheses generated from the characteristics of infected patients. These interventions included chlorhexidine preoperative shower, discontinuation of shaving, administration of antibiotics in the holding area, segregation of instruments, and implementation of an insulin protocol. Findings included a decrease in deep sternal and leg infections after implementation of these interventions. Deep sternal infection rates decreased from 2.1% to 1.5% and leg infection rates, from 1.93% to 0.47%. Results were not statistically significant but were clinically relevant. Furthermore, a total of $200,000 was achieved in cost savings in 1 year.

Education, Continuing↗
PubMed1998

Imaging the deep seismic structure beneath a mid-ocean ridge: the MELT experiment

The Mantle Electromagnetic and Tomography (MELT) Experiment was designed to distinguish between competing models of magma generation beneath mid-ocean ridges. Seismological observations demonstrate that basaltic melt is present beneath the East Pacific Rise spreading center in a broad region several hundred kilometers across and extending to depths greater than 100 kilometers, not just in a narrow region of high melt concentration beneath the spreading center, as predicted by some models. The structure of the ridge system is strongly asymmetric: mantle densities and seismic velocities are lower and seismic anisotropy is stronger to the west of the rise axis.

Journal Article↗
PubMed2004

Aftershocks driven by a high-pressure CO2 source at depth.

In northern Italy in 1997, two earthquakes of magnitudes 5.7 and 6 (separated by nine hours) marked the beginning of a sequence that lasted more than 30 days, with thousands of aftershocks including four additional events with magnitudes between 5 and 6. This normal-faulting sequence is not well explained with models of elastic stress transfer, particularly the persistence of hanging-wall seismicity that included two events with magnitudes greater than 5. Here we show that this sequence may have been driven by a fluid pressure pulse generated from the coseismic release of a known deep source of trapped high-pressure carbon dioxide (CO2). We find a strong correlation between the high-pressure front and the aftershock hypocentres over a two-week period, using precise hypocentre locations and a simple model of nonlinear diffusion. The triggering amplitude (10-20 MPa) of the pressure pulse overwhelms the typical (0.1-0.2 MPa) range from stress changes in the usual stress triggering models. We propose that aftershocks of large earthquakes in such geologic environments may be driven by the coseismic release of trapped, high-pressure fluids propagating through damaged zones created by the mainshock. This may provide a link between earthquakes, aftershocks, crust/mantle degassing and earthquake-triggered large-scale fluid flow.

Journal Article↗
PubMed2025

APNet, an explainable sparse deep learning model to discover differentially active drivers of severe COVID-19.

MOTIVATION: Computational analyses of bulk and single-cell omics provide translational insights into complex diseases, such as COVID-19, by revealing molecules, cellular phenotypes, and signalling patterns that contribute to unfavourable clinical outcomes. Current in silico approaches dovetail differential abundance, biostatistics, and machine learning, but often overlook nonlinear proteomic dynamics, like post-translational modifications, and provide limited biological interpretability beyond feature ranking. RESULTS: We introduce APNet, a novel computational pipeline that combines differential activity analysis based on SJARACNe co-expression networks with PASNet, a biologically informed sparse deep learning model, to perform explainable predictions for COVID-19 severity. The APNet driver-pathway network ingests SJARACNe co-regulation and classification weights to aid result interpretation and hypothesis generation. APNet outperforms alternative models in patient classification across three COVID-19 proteomic datasets, identifying predictive drivers and pathways, including some confirmed in single-cell omics and highlighting under-explored biomarker circuitries in COVID-19. AVAILABILITY AND IMPLEMENTATION: APNet's R, Python scripts, and Cytoscape methodologies are available at https://github.com/BiodataAnalysisGroup/APNet.

COVID-19↗
PubMed2006

Recirculatory pharmacokinetic model of the uptake, distribution, and bioavailability of prochlorperazine administered as a thermally generated aerosol in a single breath to dogs.

A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.

Aerosols↗