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PubMed2006

The staircasing effect in neighborhood filters and its solution.

Many classical image denoising methods are based on a local averaging of the color, which increases the signal/noise ratio. One of the most used algorithms is the neighborhood filter by Yaroslavsky or sigma filter by Lee, also called in a variant "SUSAN" by Smith and Brady or "Bilateral filter" by Tomasi and Manduchi. These filters replace the actual value of the color at a point by an average of all values of points which are simultaneously close in space and in color. Unfortunately, these filters show a "staircase effect," that is, the creation in the image of flat regions separated by artifact boundaries. In this paper, we first explain the staircase effect by finding the subjacent partial differntial equation (PDE) of the filter. We show that this ill-posed PDE is a variant of another famous image processing model, the Perona-Malik equation, which suffers the same artifacts. As we prove, a simple variant of the neighborhood filter solves the problem. We find the subjacent stable PDE of this variant. Finally, we apply the same correction to the recently introduced NL-means algorithm which had the same staircase effect, for the same reason.

Algorithms↗

PubMed2006

Effect of a symbiotic preparation on the clinical manifestations of irritable bowel syndrome, constipation-variant. Results of an open, uncontrolled multicenter study.

AIM: Irritable bowel syndrome (IBS) is frequently associated with an imbalance in intestinal bacteria. To date, few studies have evaluated the efficacy and safety of probiotic administration in patients with constipation-variant IBS. A new agent recently available in clinical practice is a symbiotic consisting of a probiotic, Bifidobacterium longum W11, and the short chain oligosaccharide prebiotic Fos Actilight. The aim of this study was to evaluate the efficacy and safety of this symbiotic in patients with constipation-variant IBS. METHODS: A total of 636 patients (250 men, 386 women) diagnosed with constipation-type IBS according to the Roma II criteria were enrolled in 43 centers and received the symbiotic at a dose of 3 g/die for at least 36 days. A validated questionnaire investigating symptoms and stool frequency was administered before and after treatment. RESULTS: Based on patient responses to visual scale items, frequency increased significantly after treatment in the ''no symptom'' class from 3% to 26.7% for bloating and from 8.4% to 44.1% for abdominal pain (P<0.0001). In the more severe symptoms classes (moderate-severe), symptom frequency dropped significantly from 62.9% to 9.6% and from 38.8% to 4.1% for bloating and abdominal pain, respectively. Stool frequency significantly increased from 2.9+/-1.6 times/week to 4.1+/-1.6 times/ week. CONCLUSIONS: The study product can increase stool frequency in patients with constipation-variant IBS and reduce abdominal pain and bloating in those with moderate-severe symptoms.

Abdominal Pain↗

PubMed1996

[Changes in indicators of the antioxidant defense system in patients with ischemic heart disease treated conventionally].

Parameters of antioxidant defense including superoxide dismutase, catalase and spontaneous chemiluminescence were studied in 68 patients with ischemic heart disease and 20 control patients. The above parameters decreased with the disease aggravation. Conventional therapy has improved antioxidant defense, the effect being dependent on effect of therapy irrespective of its variant.

Adrenergic beta-Antagonists↗

PubMed1998

Analysis of active site residues of the antiviral protein from summer leaves from Phytolacca americana by site-directed mutagenesis.

The summer leaf isoform of the pokeweed (Phytolacca americana) antiviral protein, PAP II, was produced in high yields from inclusion bodies in recombinant E. coli. On the basis of its sequence similarity with the spring leaf isoform (PAP I) and with the A chain of ricin, a three-dimensional model of the protein was constructed as an aid in the design of active site mutants. PAP II variants mutated in residues Asp 88 (D88N), Tyr 117 (Y117S), Glu 172 (E172Q), Arg 175 (R175H) and a combination of Asp 88 and Arg 175 (D88N/R175H) were produced in E. coli and assayed for their ability to inhibit protein synthesis in a rabbit reticulocyte lysate. All of these mutations had effects deleterious to the enzymatic activity of PAP II. The results were interpreted in the light of three reaction mechanisms proposed for ribosome-inactivating proteins (RIPs). We conclude that none of the proposed mechanisms is entirely consistent with the data presented here.

Amino Acid Sequence↗

PubMed2000

HIV-1 suppression during acute scrub-typhus infection.

BACKGROUND: In HIV-1-infected individuals, viral load has been reported to rise transiently if an acute infection with another organism occurs. Our study was prompted by the unexpected finding that HIV-1 copy number fell during an acute infection with Orientia tsutsugamushi, the causative agent of scrub typhus. METHODS: Serial HIV-1 viral load determinations were made in ten Thai adults with scrub typhus, who were not receiving antiretroviral therapy, and in five HIV-1-infected patients who had other infections (four malaria, one leptospirosis), during and after acute infections. Sera from HIV-1-infected patients with scrub typhus and from mice immunised with O. tsutsugamushi were examined for HIV-1-suppressive activity. FINDINGS: Median viral load 3 days after admission was significantly lower in the scrub-typhus group than in patients with other infections (193% vs 376% of day 28 values, p=0.03). In four O. tsutsugamushi-infected patients HIV-1 RNA copy number fell by three-fold or more compared with day 28 values, and HIV-1 copy numbers were below the assay threshold in two patients with scrub typhus. Five of seven HIV-1 isolates from non-typhus patients with CD4 lymphocytes less than 200 cells/microL were syncytia-inducing variants, whereas all ten isolates from O. tsutsugamushi-infected individuals matched by CD4-cell count were non-syncytia inducing (p=0.03). Sera from an HIV-1-negative patient with scrub typhus had potent HIV-1-suppressive activity in vitro. Sera from typhus-infected mice inhibited HIV-1 syncytia formation and bound by immunofluorescence to HIV-1-infected lymphocytes. INTERPRETATION: HIV-1-suppressive factors are produced during some scrub-typhus infection and should be investigated further in the search for novel strategies for the treatment and prevention of AIDS.

Acute Disease↗

PubMed1996

Synchrotron X-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous beta-sheet helix.

BACKGROUND: Amyloid diseases, which include Alzheimer's disease and the transmissible spongiform encephalopathies, are characterized by the extracellular deposition of abnormal protein fibrils derived from soluble precursor proteins. Although different precursors seem to generate similar fibrils, no adequate molecular structure of amyloid fibrils has been produced using modern techniques. Knowledge of the fibril structure is essential to understanding the molecular mechanism of amyloid formation and could lead to the development of agents to inhibit or reverse the process. RESULTS: The structure of amyloid fibrils from patients with familial amyloidotic polyneuropathy (FAP), which are derived from transthyretin (TTR) variants, has been investigated by fibre diffraction methods using synchrotron radiation. For the first time a significant high-angle diffraction pattern has been observed showing meridional reflections out to 2 A resolution. This pattern was fully consistent with the previously reported cross-beta structure for the fibril, but also reveals a new large scale fibre repeat of 115 A. We interpret this pattern as that of a repeating unit of 24 beta strands, which form a complete helical turn of beta sheet about an axis parallel to the fibre axis. This structure has not been observed previously. We have built a model of the protofilament of the FAP amyloid fibril based on this interpretation, composed of four beta sheets related by a single helix axis coincident with the fibre axis, and shown that it is consistent with the observed X-ray data. CONCLUSIONS: This work suggests that amyloid fibrils have a novel molecular structure consisting of beta sheets extended in regular helical twists along the length of the fibre. This implies that the polypeptide chains in the fibres are hydrogen-bonded together along the entire length of the fibres, thereby accounting for their great stability. The proposed structure of the FAP fibril requires a TTR building block that is structurally different from the native tetramer. This is likely to be either a monomer or dimer with reorganized or truncated beta sheets, suggesting that amyloid formation may require significant structural change in precursor proteins.

Amyloid↗

PubMed1955

Propagation of influenza virus in immune environments.

INFLUENZA VIRUS CAN SURVIVE, AND CAN BE PROPAGATED IN IMMUNOLOGICAL ENVIRONMENTS INDUCED IN MICE BY VACCINATION WITH THE HOMOLOGOUS STRAIN OF VIRUS: survival was associated with the emergence of variants which differed from the parent strain in antigenic characteristics. The data concerning hemagglutinating activity of the variants, on the one hand, and of the antigenicity, on the other, are compatible with the concept that the structure of the influenza virus includes a surface arrangement which is distinct from the inner virus bulk. The points (a) that propagation was accomplished with difficulty whenever the immunological environment was altered, and (b) that once established, passage was continued without difficulty, are interpreted to indicate that the mechanism of variation may involve a rearrangement of the basic hereditary mechanism.

Animals↗

PubMed2001

Bayesian prior probability distributions for internal dosimetry.

The problem of choosing a prior distribution for the Bayesian interpretation of measurements (specifically internal dosimetry measurements) is considered using a theoretical analysis and by examining historical tritium and plutonium urine bioassay data from Los Alamos. Two models for the prior probability distribution are proposed: (1) the log-normal distribution, when there is some additional information to determine the scale of the true result, and (2) the 'alpha' distribution (a simplified variant of the gamma distribution) when there is not. These models have been incorporated into version 3 of the Bayesian internal dosimetry code in use at Los Alamos (downloadable from our web site). Plutonium internal dosimetry at Los Alamos is now being done using prior probability distribution parameters determined self-consistently from population averages of Los Alamos data.

Bayes Theorem↗

PubMed2006

Thyroid tumors with a follicular growth pattern: problems in differential diagnosis.

Tumors of the thyroid characterized by a follicular growth pattern constitute the most common type of lesion of this organ encountered by pathologists. The vast majority of such lesions do not pose difficulties for histopathologic interpretation. A subset of these tumors, however, can represent a serious challenge for diagnosis. Thyroid tumors with a follicular growth pattern include a broad range of lesions that range from benign, hyperplastic nodules to follicular adenomas to follicular carcinomas. In addition, other types of tumors belonging in separate diagnostic categories can also present histologically with a follicular growth pattern, including the follicular variant of papillary thyroid carcinoma and medullary carcinoma. The histologic features and diagnostic criteria used for distinguishing among these conditions can often be subtle and subjective.

Adenocarcinoma, Follicular↗

PubMed1976

Light- and electron-microscopic studies on the formation of "dark" variants of chromaffin cells in the rat adrenal medulla.

"Dark" cell formation has been studies in the adrenal medulla with combined light- and electron-microscopic methods. Correlation between light- and electron-microscopic appearance has been demonstrated. It has been pointed out that the formation of "dark" cell artefact can be prevented during immersion fixation and can be produced also during perfusion fixation by appropriate physical conditions. "Dark" cell formation was elicited by prefixation cooling and/or by increased tissular pressure. The nature of the underlying physicochemical change was interpreted as a uniformly distributed sol-gel transition of cytoplasmic macromolecules. The formation of cytoplasmic gel structures can be considered an endothermic process which involves volume increase (+ deltaV) - as may be inferred by their susceptibility to solation by high pressure and low temperature.

Adrenal Medulla↗

PubMed2001

Thermodynamics of metal ion binding. 2. Metal ion binding by carbonic anhydrase variants.

The ability to construct molecular motifs with predictable properties in aqueous solution requires an extensive knowledge of the relationships between structure and energetics. The design of metal binding motifs is currently an area of intense interest in the bioorganic community. To date synthetic motifs designed to bind metal ions lack the remarkable affinities observed in biological systems. To better understand the structural basis of metal ion affinity, we report here the thermodynamics of binding of divalent zinc ions to wild-type and mutant carbonic anhydrases and the interpretation of these parameters in terms of structure. Mutations were made both to the direct His ligand at position 94 and to indirect, or second-shell, ligands Gln-92, Glu-117, and Thr-199. The thermodynamics of ligand binding by several mutant proteins is complicated by the development of a second zinc binding site on mutation; such effects must be considered carefully in the interpretation of thermodynamic data. In all instances modification of the protein produces a complex series of changes in both the enthalpy and entropy of ligand binding. In most cases these effects are most readily rationalized in terms of ligand and protein desolvation, rather than in terms of changes in the direct interactions of ligand and protein. Alteration of second-shell ligands, thought to function primarily by orienting the direct ligands, produces profoundly different effects on the enthalpy of binding, depending on the nature of the residue. These results suggest a range of activities for these ligands, contributing both enthalpic and entropic effects to the overall thermodynamics of binding. Together, our results demonstrate the importance of understanding relationships between structure and hydration in the construction of novel ligands and biological polymers.

Asparagine↗

PubMed2005

Combined NMR-observation of cold denaturation in supercooled water and heat denaturation enables accurate measurement of deltaC(p) of protein unfolding.

Cold and heat denaturation of the double mutant Arg 3-->Glu/Leu 66-->Glu of cold shock protein Csp of Bacillus caldolyticus was monitored using 1D (1)H NMR spectroscopy in the temperature range from -12 degrees C in supercooled water up to +70 degrees C. The fraction of unfolded protein, f (u), was determined as a function of the temperature. The data characterizing the unfolding transitions could be consistently interpreted in the framework of two-state models: cold and heat denaturation temperatures were determined to be -11 degrees C and 39 degrees C, respectively. A joint fit to both cold and heat transition data enabled the accurate spectroscopic determination of the heat capacity difference between native and denatured state, DeltaC(p) of unfolding. The approach described in this letter, or a variant thereof, is generally applicable and promises to be of value for routine studies of protein folding.

Algorithms↗

PubMed1994

Evaluation of task-oriented performance of several fully 3D PET reconstruction algorithms.

The relative performance of five fully 3D PET reconstruction algorithms is evaluated. The algorithms are a filtered backprojection (FBP) method and two variants each of the EM-ML and ART iterative methods. For each of the iterative methods, one variant makes use of voxels and the other makes use of 'blobs' (spherically symmetric functions smoothly decaying to zero at their boundaries) as basis functions in its discrete reconstruction model. The methods are evaluated from the point of view of the efficacy of the reconstructions produced by them for three typical medical tasks--estimation of the average activity inside specific regions of interest, detection of hot spots, and detection of cold spots. A free parameter is allowed in the description of each of the five algorithms; the parameters are determined by a training process during which a value of the free parameter is selected which (nearly) maximizes a technical figure of merit. Such training and the actual comparative evaluation is done by making use of randomly generated phantoms and their projection data. The methodology allows assignation of levels of statistical significance to claims of the relative superiority of one algorithm over another for a particular task. We find that using blobs as basis functions in the iterative algorithms is definitely advantageous over using voxels. This result has high statistical significance. (We also include a visual illustration of it.) Comparing FBP, EM-ML using blobs, and ART using blobs, we do not find a clear difference in the overall performance of the investigated variants of the methods. If anything, our results suggest that ART using blobs may be the most efficacious of the three.

Algorithms↗

PubMed2026

Comprehensive evaluation of AlphaFold/OpenFold prediction of experimentally unresolved proteins through novel metrics.

Predicting accurate protein structures is essential for understanding molecular mechanisms, interpreting the impact of sequence variation, and supporting translational applications ranging from drug discovery to clinical genomics. Recent advances in deep-learning-based predictors such as AlphaFold2, OpenFold, and AlphaFold3 have transformed structural biology, enabling routine in silico modeling even for challenging or previously uncharacterized proteins. However, systematic benchmarking of these tools-especially for novel targets and single amino acid variants-remains limited. Conventional global metrics often fail to capture biologically meaningful discrepancies. By evaluating multiple implementations of AlphaFold2 and OpenFold, together with ColabFold and the AlphaFold3 server, across 10 different proteins and 222 single amino acid protein variants encompassing a wide range of sizes, structures, and functions, we show that although widely used global indicators-like mean pLDDT, pTM-score, and RMSD-frequently suggest comparable performance, substantial local-level differences remain elusive. To address this gap, we introduce a comparative framework leveraging Bland-Altman agreement analysis, to evaluate per-residue Cα-confidence differences and Per-Residue profiles (PRPs), complemented by Uniform Manifold Approximation and Projection (UMAP). This approach reveals marked localized divergences, particularly within flexible or intrinsically disordered regions, where both predictor choice and single-residue substitutions trigger the largest conformational shifts. We further demonstrate that using reduced homology databases has minimal impact on predicted structural quality, offering computationally efficient alternatives. Collectively, our findings underscore the importance of integrating global and residue-specific evaluations to more accurately assess robustness, agreement, and practical usability across contemporary protein structure prediction methods.

Proteins↗

PubMed2006

Efficient Huber-Markov edge-preserving image restoration.

The regularization of the least-squares criterion is an effective approach in image restoration to reduce noise amplification. To avoid the smoothing of edges, edge-preserving regularization using a Gaussian Markov random field (GMRF) model is often used to allow realistic edge modeling and provide stable maximum a posteriori (MAP) solutions. However, this approach is computationally demanding because the introduction of a non-Gaussian image prior makes the restoration problem shift-variant. In this case, a direct solution using fast Fourier transforms (FFTs) is not possible, even when the blurring is shift-invariant. We consider a class of edge-preserving GMRF functions that are convex and have nonquadratic regions that impose less smoothing on edges. We propose a decomposition-enabled edge-preserving image restoration algorithm for maximizing the likelihood function. By decomposing the problem into two subproblems, with one shift-invariant and the other shift-variant, our algorithm exploits the sparsity of edges to define an FFT-based iteration that requires few iterations and is guaranteed to converge to the MAP estimate.

Algorithms↗

PubMed2005

Global analysis of proteins synthesized by Mycobacterium smegmatis provides direct evidence for physiological heterogeneity in stationary-phase cultures.

We have characterized the induction kinetics of approximately 1,700 proteins during entry into and survival in carbon-starved stationary phase by Mycobacterium smegmatis. Strikingly, among the patterns of expression observed were a group of proteins that were expressed in exponential-phase cultures and severely repressed in 48-h stationary-phase cultures (Spr or stationary-phase-repressed proteins) but were synthesized again at high levels in > or =128-day stationary-phase cultures (Spr(128) proteins). A number of Spr(128) proteins were identified, and they included the heat shock protein DnaK, the tricarboxylic acid cycle enzyme succinyl coenzyme A synthase, a FixA-like flavoprotein, a single-stranded DNA binding protein, and elongation factor Tu (EF-Tu). The identification of EF-Tu as an Spr(128) protein is significant, as ribosomal components are known to be expressed in a growth rate-dependent way. We interpreted these data in terms of a model whereby stationary-phase mycobacteria comprise populations of cells that differ in both their growth status and gene expression patterns. To investigate this further, we constructed gene fusions between the rpsL gene promoter (which heads the Mycobacterium smegmatis operon encoding the tuf gene encoding EF-Tu) or the rrnA promoter gene and an unstable variant of green fluorescent protein. While the majority of cells in old stationary-phase cultures had low levels of fluorescence and so rpsL expression, a small but consistently observed population of approximately 1 in 1,000 cells was highly fluorescent. This indicates that a small fraction of the cells was expressing rpsL at high levels, and we argue that this represents the growing subpopulation of cells in stationary-phase cultures.

Bacterial Proteins↗

PubMed1977

SP-10 bacteriophage-specific nucleic acid and enzyme synthesis in Bacillus subtilis W23.

Bacillus subtilis W23 was infected with a clear-plaque variant of SP-10 phage, namely, SP-10c. Exogenous thymidine was not incorporated into phage DNA (even in the presence of deoxyadenosine), nor was there any transfer of thymidine nucleotides from bacterial to viral DNA. The lytic program was unaffected by concentrations of 5-fluorodeoxyuridine sufficient to reduce bacterial DNA synthesis by greater than 95%. Although these data are consistent with the interpretation that thymidine nucleotides are excluded from phage DNA, formic acid digests of SP-10c DNA contained what appeared to be the four conventional bases; however, adenine and thymine were not recovered in equimolar yields. DNA-RNA hybridization and hybridization competition experiments were done. Synthesis of host RNA started to wane moments postinfection and stopped completely by 36 min. SP-10c coded for discrete classes of early and late RNA. The possibility of discrete subclasses of early RNA exists. Replication of the bacterial genome appeared to terminate 12 min postinfection. Degradation of the host DNA to acid-soluble material started at 36 min and, by the end of the latent period, greater than 90% of the host chromosome was hydrolyzed. Four apparent phage-coded enzymes have been identified. A di- and triphosphatase degraded dUTP, dUDP, dTTP, and dTDP (and, to a lesser extent, dCDP and d CTP) to the corresponding monophosphates; the enzyme had no apparent activity on dATP and dGTP. SP10c also coded for a DNA-dependent DNA polymerase, lysozyme, and a nuclease that degrades native bacterial DNA. Judging from the dependence of enzyme synthesis on the time of addition of rifampin (an inhibitor of the initiation of RNA synthesis), messengers for the di- and triphosphatase, as well as the nuclease, are transcribed from promoters that start to function 6 min postinfection. Promoters for polymerase and lysozyme did not become functional until 8 and 16 min postinfection, respectively.

Aminoglycosides↗

PubMed1989

Pylorus-preserving Whipple pancreaticoduodenectomy: postoperative evaluation.

The pylorus-preserving Whipple pancreaticoduodenectomy is becoming a popular alternative to the standard Whipple operation. Fluoroscopy plays an important role in postoperative assessment. The authors evaluated images of 50 consecutive patients who had undergone the newer procedure. Thirty-one complications were identified. Two normal variants that could be confused with abnormalities were noted: (a) the featureless appearance of the duodenal bulb may be mistaken for extravasation, and (b) contrastmaterial filling of the proximal jejunal loop at an end-to-end anastomosis with retained invaginated pancreas may be mistaken for intussusception. Another pitfall was failure to evaluate the pancreaticojejunostomy anastomosis fully, resulting in false-negative radiologic interpretations when leaks were present. The approach to postoperative examination of patients who have undergone the pylorus-preserving Whipple procedure is different from that of patients who have undergone the standard procedure. Radiologists should be familiar with this approach, the normal postoperative anatomy, and pitfalls in imaging so that complications can be diagnosed and treated.

Adult↗