Shape and accessible surface area of globular proteins.
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Models, Molecular↗
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Role of hydrophobicity in the binding of coenzymes. Appendix. Translational and rotational contribution to the free energy of dissociation.
We calculate the loss of surface area accessible to solvent associated with coenzyme binding in Clostridium flavodoxin, in dogfish lactate dehydrogenase, and in lobster glyceraldehyde-3-phosphate dehydrogenase. The coenzymes are nearly buried in the complexes and lose on the order of 600 A2, while the proteins lose a similar amount of accessible surface area. Some of the loss can be attributed to conformation changes in the protein, at least in the case of lactate dehydrogenase, where we show that the apoenzyme has a larger accessible surface area than the holoenzyme. Using known correlations with the hydrophobic contribution to the free energy, we demonstrate that hydrophobicity is the major source of stabilization free energy in FMN binding to flavodoxin and in NAD binding to the two dehydrogenases: it contributes 25 to 30 kcal/mol to the free energy of dissociation, more than required in order to compensate for the loss of six degrees of translational/rotational freedom by the coenzyme.
Animals↗
Platelet lysis and aggregation in shear fields.
A rotational viscometer was used to study the effects of shear stress on platelets in human platelet-rich plasma (PRP). For 5-min exposure times, shear stresses above 160 dynes/cm2 induced platelet lysis (as determined by release of platelet lactic dehydrogenase). For 30-s exposure times, shear stresses greater than 600 dynes/cm2 were required to induce platelet lysis. The platelet counts of sheared PRP were decreased to as low as one-fifth the original count due largely to shear-induced aggregation. The count is a minimum at intermediate stress levels (200-400 dynes/cm2). Higher stresses induce disaggregation as well as lysis. The diminution in the counts was partially reversed in 2 h incubation after cessation of shearing. Experiments were carried out with three different viscometer configurations so that the shear stress and the solid surface area access could be varied independently. Surface access was not a significant variable in the conditions of the experiments. Thus aggregation and lysis may be induced by stress effects alone as well as by solid surface effects. The results also show that the response of platelets to shear stress is strongly dependent on exposure time. Platelets are much less resistant to shear stress than red cells for relatively long exposure times. However, the converse is true for very short exposure times.
Blood Platelets↗
AlphaFold2, SPINE-X, and Seder on Four Hard CASP Targets.
We analyzed four cases from the CASP15 experiment with low prediction accuracy and compared AlphaFold2, SPINE-X, and Seder on these cases. We find that overall, AlphaFold2 performs better than SPINE-X in predicting secondary structure (SS) and solvent accessible surface area (ASA). For some cases, SPINE-X better predicts sheet and coil regions. We also find that AlphaFold2 is better than Seder in selecting the best matching tertiary structure model for one case and is worse in another case. For two cases Alphafold2 and Seder selected the same models. From the cases presented here, it appears that AlphaFold2 predicts more compact structures than the native one. We find that while, as widely reported, AlphaFold2 significantly improved protein tertiary structure prediction, there are cases, such as the four presented here, for which the tertiary structure prediction could still be significantly enhanced. The source code, license, and documentation for SPINE-X and Seder are available from Research and Information Systems, LLC at http://mamiris.com .
Software↗
In silico identification of DNMT1 inhibitors from the PlantCyc database through computational approach to assess the anti-cancer potential of nutraceutical compounds in breast cancer.
Breast cancer accounts for a disproportionate share of global cancer-related deaths, with 670,000 fatalities and 2.3 million new diagnoses recorded in women during 2022 alone. Existing treatment modalities carry considerable toxicity burdens, and resistance to available agents remains an unresolved clinical problem. DNA methyltransferase 1 (DNMT1), the enzyme chiefly responsible for maintaining genome-wide methylation patterns during DNA replication, has been mapped out as a high-value target in breast cancer because its dysregulation silences tumour suppressor genes through promoter hypermethylation. The present work involves hierarchical in silico workflow to screen 4549 plant-derived compounds from the PlantCyc database (v16.0.3) against the human DNMT1 catalytic domain (PDB ID: 4WXX). Ten top-scoring compounds were taken forward for molecular docking via AutoDock Vina; Quercetin and Kaempferol both recorded the highest binding affinities at -9.5 kcal/mol, Wogonin (-9.3 kcal/mol) and Xanthohumol (-8.1 kcal/mol) also emerged as strong binders. Pharmacokinetic evaluation using ADMET-AI confirmed that all 10 compounds met Lipinski's rule of five, with human intestinal absorption values at or above 0.98. Wogonin and Xanthohumol were selected for a 100 ns all-atom molecular dynamics (MD) simulation in GROMACS due to their well-rounded ADMET profiles and limited existing data on their specific interactions with DNMT1 in breast cancer. Across all measured trajectory metrics, backbone RMSD, residue fluctuation, radius of gyration, solvent-accessible surface area, and intermolecular hydrogen bond count, Wogonin formed a more stable, compact complex. These findings suggest that Wogonin and Xanthohumol are non-toxic nutraceutical candidates suitable for DNMT1 targeted epigenetic therapy, with computational foundation strong enough to facilitate future in vitro and in vivo validation work.
Humans↗
Equilibrium penetration of monolayers IV: dipalmitoyllecithin-centrimonium bromide system.
Equilibrium surface pressure-area isotherms of dipalmitoyllecithin monolayers were measured on substrates containing various concentrations of the surfactant, cetrimonium (hexadecyltrimethylammonium) bromide. From these isotherms, the saturation adsorptions of surfactant for various surface lecithin concentrations were calculated. Plotting of these adsorptions against the inverse of the area per lecithin molecule, as required for the "accessible area" theory, revealed two linear segments, corresponding to penetrating at high and at low monolayer areas. At both high and low areas, the adsorption into the accessible areas of the surface was similar to adsorption at a monolayer-free surface. The effective cross-sectional area of the monolayer molecule in the low area region was equal to the collapse area; in the high area region, it was equal to an area corresponding to the co-area, as calculated from the Amagat equation. The change in cross-sectional area corresponded to the transition in the monolayer from a liquid condensed state to a liquid expanded state.
Adsorption↗
Veterinary toxicology: the epidemiology of poisonings in domestic animals.
Animals are constantly exposed to a wide variety of foreign chemicals, many of which are potentially toxic and some of which result in the clinical poisonings. Pesticides are applied on or around animals for the control of insects and rodents. These chemicals may be placed in areas without regard for accessibility to household pets and domestic livestock. Insecticides, herbicides, and fungicides are routinely and haphazardly applied to animal and environmental surfaces alike with apparent disregard for differences in absorptive capability. Fortunately, newer herbicides and fungicides are relatively nonhazardous. Drugs are considered to have therapeutic effects, but the lay and professional person's disregard for species differences and variations in recommended dosages can result in poisonings. Adverse reactions may be misnomers for errors in judgment. Failure to provide satisfactory storage facilities for animal feeds and the improper preservation and handling of feedstuffs allow the growth and development of a variety of mycotoxins. Ignorance on the part of animal owners and livestockmen can result in a number of unusual and sometimes fatal clinical syndromes. The dependence of domestic animals and livestock upon their owners for the total environment makes these animals extremely susceptible to environmental pollutants. Exposure to noxious gases, irritating and hazardous industrial materials and wastes, water contaminants, and casually discarded compounds of our own use can and frequently do result in animal illnesses and death. Persons responsible for animals may be unaware of the potential hazard or lack good judgment in the use of these chemicals. Forceful and continuing education for the safe and sensible use of all foreign compounds on and around domestic animals and livestock is needed. Persons handling and applying these materials must recognize their responsibility, not only to themselves but also to their neighbors and the animals in their care.
Animal Feed↗
Agarose-encapsulated adsorbents.
A method is described for the encapsulation of ion-exchange and adsorbent resins of native particle diameter 0.2-1.0 mm into agarose spheres of diameter 5-10 mm. Plasma components diffuse rapidly through the agarose coating, but blood corpuscles have no direct access to the resins. At least 0.3 g of resin can be incorporated into 1 g of the agarose beads, so that the effective surface area with regard to erythrocytes, thrombocytes, and leucocytes is reduced by a factor of at least 5, and up to 20, depending on the native resin particle size. Pulverised active charcoal, or resins in powder form can also be encapsulated in this manner. The haemocompatibility of the agarose coating seems to be considerably more acceptable than that of the adsorbents in their native state.
Adsorption↗
Rectal papillae in Musca domestica: the cuticle and lateral membranes.
The role of specialized regions of insect rectal papillae in the regulation of water and ion uptake is well documented. Although the apparatus for active uptake of water or ions is located in various cell membranes, the absorbed molecules must first pass through the cuticle which lines the rectal epithelium. Most cuticle (e.g. abdominal) has been shown to be permeable only to molecules soluble in wax, and to be impermeable to water and ions. Obviously if such cuticle lined the rectum, absorption of water and ions would be severely restricted. The present freeze-fracture and lanthanum tracer study was undertaken to investigate in more detail both the morphological features of the rectal papillae cuticle which could be responsible for its anomalous permeability and the various cell membranes involved in this transport. It has been suggested from permeability studies that the anomalous permeability of rectal papillae cuticle could be due to the lack of a complete wax layer over the surface of the rectal cuticle. The present study strongly supports this suggestion. Thus, the freeze-fracture micrographs have shown that a surface layer of the cuticle reacts during fracturing like a lipid bilayer. However, in rectal papilla cuticle this surface bilayer is interrupted at each epicuticular depression by areas of different fracturing behaviour. These discontinuities in the surface bilayer probably allow the rectal contents to contact directly the true cuticular matrix. They could, therefore, explain the case with which water and ions penetrate the rectal cuticle and so gain access to the underlying epithelial cells. Although similar discontinuities are present on some of the rectal cuticle surface external to the rectal papillae, they appear to be filled in by plugs of lipid-like material. The lateral plasma membranes of the rectal papillae cells are generally considered to be the main site of active transport. The present lanthanum tracer and freeze-fracture study has shown that the lateral plasma membranes contain 3 distinct differentiations. Septate junctions are present at the apical and basal surfaces of the epithelial layer; a further membrane differentiation is found adjacent to the septate junctions; and thirdly, an array of short, variable length, non-anastomosing linear structures covers most of the lateral plasma membrane surface. These latter structures, unlike known types of cell junctions do not show equivalent arrays in apposing membranes even when the lateral plasma membranes of adjacent cells are closely apposed. The possible function of these structures is discussed.
Animals↗
The role of cytoskeleton in adreno-medullary secretion.
Chromaffin cells of the adrenal medulla contain prominent arrays of microtubules and microfilaments. One population of microtubules radiates from the cytocentrum and permeates the areas of the cytoplasm containing chromaffin granules; the other population of microtubules forms a subplasmalemmal network together with actin-like microfilaments. Hence, the cytoskeletal elements in chromaffin cells are strategically located to participate in the mobility of chromaffin granules to the cell surface and to regulate access of the granules to the plasma membrane during exocytosis. Agents which effect the integrity of the cytoskeleton clearly affect the secretory process in a manner which indicates that the microtubules and microfilaments play an active role in the release process.
Adrenal Medulla↗
[Meaningful possibilities of palliative therapy of incurable mouth and pharyngeal neoplasms and their recurrence].
In incurable cancer of the mouth and oropharynx, reasonable palliative therapy should render the patient's remaining life-span worth living. The following problems impair tumor patient's well-being: 1. pain, 2. ingestive and respiratory difficulties, 3. aspect, 4. odor, 5. psychic trauma resulting from 3 and 4. Pain, either caused by the tumor itself or as a reaction to irradiation or inflammatory response, is of primary importance. Impairment of ingestion, respiration, and speech diminishes the quality of life. Disfigurement of the face or a penetrating odor may sometimes cause additional psychic stress. Besides palliative radio- and chemotherapy, in certain cases palliation can be obtained by surgery, which may reduce the size of a cosmetically disturbing tumor mass or create a clean wound surface easier to care for than a necrotic surface. Furthermore, painful neuralgic nerve branches may be severed. Severe lymphedema of the face and neck may be improved by lumbo-peritoneal shunt operation. Most recently, cryosurgery has won an established place in the management of these problems, although certain restrictions must be observed. Superficial recurrences can be treated without further mutilation of the patient. Painful areas of the tumor can be eradicated. Recurrences in the hypopharynx, which are accessible with difficulty only, can be treated with a cryosonde with little harm to an already impaired patient. Multiple tumor lesions can be iced at the same time. Among the reasonable palliative methods of treatment, synchronized irradiation and chemotherapy as well as implantation of solid radioactive substances must be mentioned.
Analgesia↗
Computer optimization of enteral hyperalimentation.
A computer program has been developed to allow the generation of written orders for the logical progression of enteral hyperalimentation by the technique of continuous nasogastric infusion. Data required for entry include name, age, sex, height, usual and current weights, degree of stress, and if indicated, restrictions of nitrogen, fluids, sodium and potassium. A specific formulation may be requested, or the computer will pick a single nutrient solution or combination of two solutions that will best meet the requested constraints. Output includes entered data with English and Metric interconversion, surface area, and estimates of basal energy expenditure, protein wastage, protein and caloric requirements. If requested, daily orders are written to include a reasonable progression of infusion rates and concentrations of the solutions(s). Daily values are printed for the total amounts to be infused of fluid, calories, protein, sodium, potassium, and mOsm. The programs have been demonstrated to run in either on-line or batch mode. The system is easily accessible by physician, dietician, nurse, or other interested professionals.
Adult↗
A pharmacological approach to the structure of sodium channels in myelinated axons.
Figure 6 summarizes the present state of our knowledge on the sodium channel in myelinated nerve fibers. Two sites have been discussed in detail: a metal cation binding site accessible by tetrodotoxin and saxitoxin from the outside surface only; and a second site accessible from the inside surface with which local anesthetics combine. Hydrogen ions gain access to this region of the sodium channel (and hence determine the relative local concentration of protonated drug) more readily from the extracellular fluid than from the axoplasm (Schwarz et al 1977). In addition, a variety of other sites have been mentioned, binding of drugs to which alters selectively the kinetics of opening and closing of the h and m gates. In myelinated nerve fibers these channels are packed tightly on the nodal membrane. The highest estimate for the sodium channel density in the mammalian node is 10,000 micron2. A re-evaluation of the effective nodal area, however, might reduce this value to 3000-5000/micron 2. This would still leave the nodal membrane rather crowded with sodium channels. Furthermore, the channel density would still be greater than the density of particles, sometimes believed to be sodium channels seen in freeze fracture studies (Rosenbluth 1976). One possibility for resolving this problem is that the units detected by X-ray inactivation (Levinson & Ellory 1973), and those seen in freeze-fracture studies (Rosenbluth 1976) represent not single sodium channels but groups of three. Catterall & Morrow (1978) in a comparison of the binding of saxitoxin and Leiurus sculpturatus scorpion toxin venom have concluded that there are three saxitoxin binding sites for each scorpion toxin binding site. On this basis, three saxitoxin molecules might act to block independently each of the three openings of the channels; while the the conformational change produced by the scorpion venom molecule would affect the inactivation process of all three channels.
Aconitine↗
Sealing quality of a temporary filling material.
Endodontic access cavities were prepared in forty extracted human teeth. The access cavities were obturated with Cavit and tested for leakage with methylene blue. The data suggested that at least a 3.5 mm. thickness of Cavit should be used in order to prevent leakage. Examination under the scanning electron microscope showed areas in which the constituents of Cavit were improperly mixed, which may lead to increased penetration.
Dental Cavity Preparation↗
Adaptation of marrow sinus wall to fluctuation in the rate of cell delivery: studies in rabbits after blood-letting.
The extent of marrow sinus wall coverage by perisinal adventitial cells was measured before and after removing 25% of the calculated blood volume in rabbits. A marked reduction in the area covered by adventitial cells was recorded coinciding with the early reticulocyte response to phlebotomy. In control animals, only scattered microfilaments were occasionally observed in the cytoplasmic process of adventitial cells. After phlebotomy, these filaments were more frequently observed and appeared as band-like structures, raising the possibility of an active role for perisinal adventitial cells in response to fluctuations in the magnitude of cell traffic. Perisinal adventitial cells may, therefore, translate the body's demand for cell delivery by regulating the rate of transmural cell migration from the marrow. Such an adaptive mechanism may depend on the incompleteness of the adventitial layer of the sinus wall and the absence of endothelial-adventitial cell junctions, permitting separation of the two layers of the wall, so that the reticulocyte can gain access to more endothelial surface and the pores.
Adaptation, Physiological↗
Rapid accumulation of cholesterol in serum, liver and aorta of Japanese quail.
Five-week-old, male, Japanese quail (Coturnix coturnix japonica) were given ad lib. access to either a glucose-soybean meal diet with 10% fat and 1% cholesterol (inducer) diet, or a corn-soybean meal (control) diet for 10 weeks. At the beginning of the experiment, and at two week intervals thereafter, quail from each treatment were killed, and the cholesterol concentrations of serum, aorta, and liver, as well as the extent of lipid accumulation in the intima of the aortas were determined. The cholesterol concentration of the serum, aorta, and liver of the control birds remained constant throughout the experiment, while the cholesterol concentration of these organs from birds fed the inducer diet were markedly elevated. At the conclusion of the experiment, the cholesterol concentrations of the serum and liver of birds fed the inducer diet were 6.7 and 14.4 times greater, respectively, than those from the control-fed birds. Approximately 45% of the aortas from the birds fed the inducer diet exhibited moderate to severe (greater than 25% of surface area covered) lipid accumulations at 10 weeks. The rate of cholesterol accumulation appeared to be more rapid than has been reported previously for this species.
Animals↗
Studies of glutamate dehydrogenase: analysis of functional areas and functional groups.
1. It is shown by limited tryptic digestion of beef liver glutamate dehydrogenase under native conditions that the amino terminus of the polypeptide chain is located at the surface of the molecule. End-group analysis after trypsin treatment yields aspartic acid as the new N-terminal amino acid while the C-terminal threonine remains unchanged. 2. NADH, especially in the presence of 2-oxoglutarate, protects the enzyme against tryptic degradation. In the absence of the coenzyme, glutamate dehydrogenase is rapidly inactivated. 3. The regulatory effects of ADP and GTP are only slightly altered by trypsin. A small shift of the pH dependence of the activation by ADP is observed. 4. The quaternary structure of the unimer of the enzyme is not affected by limited tryptic digestion indicating that the N-terminal part of the polypeptide chain is not located in the contact domains between the polypeptide chains. The association of the hexamer to large associated particles is reduced but not abolished. 5. It is shown by treatment of the enzyme with iodo[2(-14)C]acetic acid as well as with Ellman's reagent that the six - SH groups of the polypeptide chain are buried and not accessible to these reagents in phosphate buffer. In Tris buffer they become exposed and react in the order 89, 55, 197, 115, 270, 319. This together with the result that in Tris buffer the rat of inactivation caused by trypsin is higher than in phosphate buffer indicates that Tris buffer changes drastically the properties of the enzyme. 6. Cross-linking of the enzyme molecule with bifunctional reagents and subsequent dodecylsulfate-polyacrylamide electrophoresis shows that the six identical polypeptide chains are arranged in two groups of three. 7. The implications of these results for the tertiary and quaternary structure of beef liver glutamate dehydrogenase are discussed.
Animals↗
Evaluation of craniofacial surgery in the treatment of facial deformities.
Surgical access to the cranial, orbital, and facial areas, as developed by Tessier, has produced not only definitive repair of previously uncorrectable congenital deformities such as orbital hypertelorism and facial stenosis (e.g., Crouzon's, Apert's syndromes) but also has improved markedly the treatment of traumatic and neoplastic defects. The surgical approach allows complete dissection of facial soft tisses including the orbits from the underlying bones followed by corrective osteotomies and fixation. Mobilization of the frontal lobes through a frontal bone flap exposure may be required. The ramifications of this latest intrusion by surgeons into a previously inviolate anatomic area have involved neurosurgeons, ophthalmologists, anesthesiologists, and dental and psycho-social disciplines. The disciplines of genetics and embryology are being influenced by this new field of surgery, much as the study of immunology was influenced by transplantation surgery two decades ago. This report analyzes a 10 year experience with over 100 patients with emphasis on patient selection by disease, age, intellectual status, morbidity, complications, and the psycho-social reactions of patient and family. Procedures initially planned to correct dental and aesthetic defects are proving beneficial for other functions including hearing, taste and smell, articulation and tongue movement, respiratory function, vision, and possibly bone growth. The development of self image, a normal process always in operation, is also strikingly altered. These operations may last as long as 14 to 16 hours. We have had no deaths or postoperative blindness. One postoperative cerebrospinal fluid leak was successfully repaired. Three partial losses of bone grafts and four instances of late cellulitis have occurred. Prevention of infection seems related to avoidance of dead spaces and primary closure of all mucosal, dural, conjunctival and skin surfaces.
Adolescent↗