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Discontinuous translation and mRNA secondary structure.

It has recently been reported that ribosomes pause at specific sites during translation of the chloroplast photosystem II reaction center protein D1(1). We have obtained the stability map of local secondary structure of the mRNA of psbA gene, encoding for D1, by plotting the free energy of the optimal secondary structure of the local segment of the mRNA against the segment position along a base sequence of the mRNA. It was found that the positions of minima or lower free energy in the map coincide with the positions of the pausing sites during synthesis of D1. The result suggests that synthesis pauses of D1 could-be induced by the mRNA secondary structure.

Hordeum↗

Effect of compression on the global optimization of atomic clusters

Recently, Locatelli and Schoen proposed a transformation of the potential energy that aids the global optimization of Lennard-Jones clusters with nonicosahedral global minima. These cases are particularly difficult to optimize because the potential energy surface has a double funnel topography with the global minimum at the bottom of the narrower funnel. Here we analyze the effect of this type of transformation on the topography of the potential energy surface. The transformation, which physically corresponds to a compression of the cluster, first reduces the number of stationary points on the potential energy surface. Secondly, we show that for a 38-atom cluster with a face-centered-cubic global minimum the transformation causes the potential energy surface to become increasingly dominated by the funnel associated with the global minimum. The transformation has been incorporated in the basin-hopping algorithm using a two-phase approach.

Journal Article↗

A fast procedure for optimizing dynamic force distribution in multifingered grasping.

This correspondence deals with the dynamic force distribution (DFD) problem, i.e., computing the contact forces to equilibrate a dynamic external wrench on the grasped object. The sum of the normal force components is minimized for enhancing safety and saving energy. By this optimality criterion, the DFD problem can be transformed into a linear programming (LP) problem. Its objective function is the inner product of the dynamic external wrench and a vector, and the constraints on the vector, given by a set of linear inequalities, define a polytope. The solution to the LP problem can always be attained at the vertex of the polytope called the solution vertex. We notice that the polytope is determined by the grasp configuration. Along with the direction change of the dynamic external wrench, only the solution vertex moves to an adjacent vertex sequentially, whereas the polytope with all its vertices remains unchanged. Therefore, the polytope and the adjacencies of each vertex can be computed in the offline phase. Then, in the online phase, simply search the adjacencies of the old solution vertex for the new one. Without lost of optimality, such a DFD algorithm runs a thousandfold faster than solving the LP problem by the simplex method in real time.

Fingers↗

Theoretical investigation of electron transfer transition in tetracyanoethylene-contained organic complexes.

In this work, the authors use complete active space self-consistent field method to investigate the photoinduced charge-separated states and the electron transfer transition in complexes ethylene-tetracyanoethylene and tetramethylethylene-tetracyanoethylene. Geometries of isolated tetracyanoethylene, ethylene, and tetramethylethylene have been optimized. The ground state and the low-lying excited states of ethylene and tetracyanoethylene have been optimized. The state energies in the gas phase have been obtained and compared with the experimentally observed values. The torsion barrier of tetracyanoethylene has been investigated through the state energy calculation at different conformations. Attention has been particularly paid to the charge-separated states and the electron transfer transition of complexes. The stacked conformations of the donor-acceptor complexes have been chosen for the optimization of the ground and low-lying excited states. Equilibrium solvation has been considered by means of conductor-like screening model both in water and in dichloromethane. It has been found that the donor and tetracyanoethylene remain neutral in complexes in ground state (1)A(1) and in lowest triplet state (3)B(1), but charge separation appears in excited singlet state (1)B(1). Through the correction of nonequilibrium solvation energy based on the spherical cavity approximation, pi-->pi* electron transfer transition energies have been obtained. Compared with the experimental measurements in dichloromethane, the theoretical results in the same solvent are found higher by about 0.5 eV.

Journal Article↗

optiPRM: A Targeted Immunopeptidomics LC-MS Workflow With Ultra-High Sensitivity for the Detection of Mutation-Derived Tumor Neoepitopes From Limited Input Material.

Personalized cancer immunotherapies such as therapeutic vaccines and adoptive transfer of T cell receptor-transgenic T cells rely on the presentation of tumor-specific peptides by human leukocyte antigen class I molecules to cytotoxic T cells. Such neoepitopes can for example arise from somatic mutations and their identification is crucial for the rational design of new therapeutic interventions. Liquid chromatography mass spectrometry (LC-MS)-based immunopeptidomics is the only method to directly prove actual peptide presentation and we have developed a parameter optimization workflow to tune targeted assays for maximum detection sensitivity on a per peptide basis, termed optiPRM. Optimization of collision energy using optiPRM allows for the improved detection of low abundant peptides that are very hard to detect using standard parameters. Applying this to immunopeptidomics, we detected a neoepitope in a patient-derived xenograft from as little as 2.5 × 106 cells input. Application of the workflow on small patient tumor samples allowed for the detection of five mutation-derived neoepitopes in three patients. One neoepitope was confirmed to be recognized by patient T cells. In conclusion, optiPRM, a targeted MS workflow reaching ultra-high sensitivity by per peptide parameter optimization, makes the identification of actionable neoepitopes possible from sample sizes usually available in the clinic.

Humans↗

Doping dependence of the coupling of electrons to bosonic modes in the single-layer high-temperature Bi2Sr2CuO6 superconductor.

A recent highlight in the study of high-T(c) superconductors is the observation of band renormalization or self-energy effects on the quasiparticles. This is seen in the form of kinks in the quasiparticle dispersions as measured by photoemission and interpreted as signatures of collective bosonic modes coupling to the electrons. Here we compare for the first time the self-energies in an optimally doped and strongly overdoped, nonsuperconducting single-layer Bi-cuprate (Bi2Sr2CuO6). In addition to the appearance of a strong overall weakening, we also find that the weight of the self-energy in the overdoped system shifts to higher energies. We present evidence that this is related to a change in the coupling to c-axis phonons due to the rapid change of the c-axis screening in this doping range.

Journal Article↗

Isomers of C(20): an energy profile.

Semiempirical calucaltions, at the PM 3 level, are used to geometrically optimize and determine the absolute energies (heats of formation) of a variety of C(20) isomers. Based on the geometrically optimized Cartesian coordinates of the ring and the bowl isomers, and the subsequent saddle-point calculation, a two-dimensional energy profile between these two isomers is generated. Performing geometry optimization on the Cartesian coordinates that correspond to energy minima within the ring-bowl profile, we have been able to identify several more isomers of C(20) that are predicted to be energitically stable. With these additional stable structures, we have identified pairs of isomers that lie adjacent to one another on the potential energy surface, as is evidenced by the form of their respective energy profiles. These adjacent pairs of isomers establish a step-wise transformation between the ring and the bowl. This process, which extends out over the three-dimensional surface, is predicted to require less energy than that of the direct, two-dimensional transformation predicted in the ring-bowl profile.

Journal Article↗

Fluid and electrolyte therapy in ruminants.

Five important questions always must be asked and answered regarding fluid and electrolyte therapy in ruminants: (1) Is therapy needed? (2) What type of therapy? (3) What route of administration? (4) How much should be administered? and (5) How fast should the solution be administered? Food animal veterinarians routinely should carry the following commercially available crystalloid solutions and have the knowledge of how to use the products appropriately: Ringer's solution, 1.3% NaHCO3, acetated Ringer's solution, HS (7.2% NaCl), 8% NaHCO3, 23% calcium gluconate, calcium-magnesium solutions, and 50% dextrose. Ruminants with a blood pH less than 7.20 should be treated intravenously with 1.3% or 8.0% NaHCO3, and those animals with a blood pH greater than 7.45 should be treated intravenously with Ringer's solution. Oral electrolyte solutions or intravenous acetated Ringer's solution should be administered to ruminants with a blood pH greater than 7.20 but less than 7.45, and acetated Ringer's solution is preferred to lactated Ringer's solution. HS solution should be administered whenever rapid resuscitation is required. Oral administration of electrolyte solutions is underused in neonatal and adult ruminants. The optimal solution for oral administration to neonatal ruminants has a sodium concentration between 90 and 130 mmol/L; a potassium concentration between 10 and 20 mmol/L; a chloride concentration between 40 and 80 mmol/L; 40 to 80 mmol/L of metabolizable (nonbicarbonate) base, such as acetate or propionate; and glucose as an energy source. The optimal formulation for adult ruminants is unknown, but such a solution should contain sodium, potassium, calcium, magnesium, phosphate, and propionate to facilitate sodium absorption and to provide an additional source of energy to the animal. Acidemia is treated best by intravenous or oral administration of NaHCO3. Alkalemia is treated best by intravenous administration of Ringer's solution and oral administration of chloride-rich electrolytes such as KCl; the latter provides a physiologically more appropriate treatment than oral administration of vinegar or acetic acid solutions. Hypocalcemia is treated best by administering intravenous calcium borogluconate solutions or oral CaCl2 gels. Hypomagnesemia is treated best by intravenous or subcutaneous administration of combined calcium and magnesium solutions. Hypophosphatemia is treated best by oral administration of feed-grade monosodium phosphate. Hypokalemia is treated best by oral administration of feed-grade KCl; hyperkalemia is treated best by intravenous administration of 8.0% NaHCO3 or HS. The major challenges in treating fluid and electrolyte disorders in ruminants are making treatment protocols more practical and less expensive and formulating an optimal electrolyte solution for oral administration to adult ruminants.

Animals↗

Implementation and quantitative evaluation of analytical methods for attenuation correction in SPECT: a phantom study.

Three differing exact methods of inverting the two-dimensional (2D) exponential Radon transform were implemented and evaluated quantitatively with a phantom study. The phantom had the shape of a pie-chart divided into six cavities, each 480 ml in volume and 10 cm in height, that were symmetrically positioned in a cylinder that was 20 cm in diameter and 10 cm in height. This phantom tests for linearity between true activity concentration and measured activity concentration, and it is denoted as a linearity phantom in the present study. Each cavity contained a different concentration of a homogeneous solution of 99mTc (74, 148, 222, 296, 370 and 444 kBq ml(-1)). Data acquisition was performed with two energy windows: a 20% photopeak energy window set symmetrically over the 140 keV of 99mTc and a secondary 5% energy window set over the 122 keV peak. We optimized a triple-energy window scatter correction method for a gamma camera-collimator system to obtain accurate scatter-corrected projections. A circular ROI 3 cm in diameter was identified over each cavity region, and count density (counts per pixel) was calculated. This value was converted to activity concentration (kBq ml(-1)) using a cross-calibration coefficient between SPECT counts and the gamma well counter. The relation between true activity (x) and measured activity concentration (y) was fitted to a line using the least-squares method. Regression lines were y = 0.63 + 1.0255x (R2 = 0.9987), y = -2.62 + 1.0278x (R2 = 0.9995), and y = 0.092 + 1.0241x (R2 = 0.9989) for the Bellini, Inouye and Metz-Pan methods respectively. In another phantom study using two different types of phantoms, contrast of a cold region in the two was 96% and 101% for all three methods. Combined optimized scatter correction and analytical attenuation correction methods achieve good accuracy in quantification of activity distribution with a uniform attenuating medium.

Humans↗

The heats of formation of diazene, hydrazine, N2H3+, N2H5+, N2H, and N2H3 and the Methyl Derivatives CH3NNH, CH3NNCH3, and CH3HNNHCH3.

The heats of formation of N(2)H, diazene (cis- and trans-N(2)H(2)), N(2)H(3), and hydrazine (N(2)H(4)), as well as their protonated species (diazenium, N(2)H(3)(+), and hydrazinium, N(2)H(5)(+)), have been calculated by using high level electronic structure theory. Energies were calculated by using coupled cluster theory with a perturbative treatment of the triple excitations (CCSD(T)) and employing augmented correlation consistent basis sets (aug-cc-pVnZ) up to quintuple-zeta, to perform a complete basis set extrapolation for the energy. Geometries were optimized at the CCSD(T) level with the aug-cc-pVDZ and aug-cc-pVTZ basis sets. Core-valence and scalar relativistic corrections were included, as well as scaled zero point energies. We find the following heats of formation (kcal/mol) at 0 (298) K: DeltaH(f)(N(2)H) = 60.8 (60.1); DeltaH(f)(cis-N(2)H(2)) = 54.9 (53.2); DeltaH(f)(trans-N(2)H(2)) = 49.9 (48.1) versus >/=48.8 +/- 0.5 (exptl, 0 K); DeltaH(f)(N(2)H(4)) = 26.6 (23.1) versus 22.8 +/- 0.2 (exptl, 298 K); DeltaH(f)(N(2)H(3)) = 56.2 (53.6); DeltaH(f)(N(2)H(3)(+)) = 231.6 (228.9); and DeltaH(f)(N(2)H(5)(+)) = 187.1 (182.7). In addition, we calculated the heats of formation of CH(3)NH(2), CH(3)NNH, and CH(3)HNNHCH(3) by using isodesmic reactions and at the G3(MP2) level. The calculated results for the hydrogenation reaction RNNR + H(2) --> RHNNHR show that substitution of an organic substituent for H improved the energetics, suggesting that these types of compounds may be possible to use in a chemical hydrogen storage system.

Journal Article↗

Color mammography. Image generation and receiver operating characteristic evaluation.

Color mammography is a technique whereby dual-energy mammographic image data are used to calculate a calcium image; the calcium image is colorized and overlaid onto the conventional (lower energy) gray scale mammogram for radiologist viewing. This technique is presented as a practical way to use the increased calcium sensitivity of dual-energy mammography without requiring an increase in the number of images that the radiologist must read, and without subjecting the radiologist to the unfamiliar appearance of the dual-energy subtracted images. Using straightforward imaging theory, the acquisition techniques for both conventional and dual-energy mammography were optimized, and the optimal technique factors were used to generate a series of computer-simulated mammographic images that were used in a receiver operating characteristic (ROC) comparative study. Ideal observer ROC experiments indicate that (dual-energy) calcium images yield consistently higher sensitivity and specificity to the presence of calcifications, regardless of the amount of tissue "clutter," whereas conventional mammography results show degraded detectability performance as tissue contrast increases. Using human observers viewing simulated images, color mammography delivered greater calcification detectability than conventional mammography.

Breast Diseases↗

Ontogenesis of ultrastructural features during osteogenic differentiation in diffusion chamber cultures of marrow cells.

Three stages of osteogenic differentiation can be identified in in vivo diffusion chamber cultures (DCC) of unselected marrow cells, namely, proliferation, differentiation, and maturation (mineralization). These stages were characterized correlatively by in situ differential cell counts, alkaline phosphatase activity, and mineral accumulation. In the present study, the ultrastructure of marrow cell DCC was examined after incubation for 3-21 days. Features characteristic of osteoblastic and chondroblastic differentiation were first noted in 12 day DCC. Sites of osteoblastic differentiation showed cell-cell contacts associated with an increased cell density. The osteoblastic cells had long processes and were embedded in matrix with prominent fiber bundles reminiscent of collagen type I. The chondroblastic cells appeared solitary in areas of lesser cell density. By contrast to the long osteoblastic cell processes, they had short plasmalemmal projections and the matrix surrounding them contained single, thin, short fibers reminiscent of collagen type II, as well as proteoglycan granules. Both cell types showed prominent cytoskeletal elements, rough endoplasmic reticulum, and Golgi. One finding, previously unnoted in differentiating osteogenic cells, was mitochondria with condensed cristae that represent an increased rate of energy metabolism. These mitochondria were particularly abundant in the differentiation stage and declined as the cultures matured. These findings, together with previous reports in the epiphyseal growth plate, suggest that mineralization is associated with an optimal level of energy metabolism rather than extreme hypo- or hyperoxia. The set of ultrastructural parameters defined here in the marrow cell DCC may serve as useful markers for cells undergoing osteogenic differentiation.

Animals↗

The tetracycline: Mg2+ complex: a molecular mechanics force field.

Tetracycline (Tc) is an important antibiotic, which binds specifically to the ribosome and several proteins, in the form of a Tc-:Mg2+ complex. To model Tc:protein and Tc:RNA interactions, we have developed a molecular mechanics force field model of Tc, which is consistent with the CHARMM force field for proteins and nucleic acids. We used structures from the Cambridge Crystallographic Data Base to identify the main Tc conformations that are likely to be present in solution and in biomolecular complexes. A conformational search was also done, using the MM3 force field to perform simulated annealing of Tc. Several resulting, low-energy structures were optimized with an ab initio model and used in developing the new Tc force field. Atomic charges and Lennard-Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with Tc at 36 different positions. We considered both a neutral and a zwitterionic Tc form, with and without bound Mg2+. The final rms deviation between the ab initio and force field energies, averaged over all forms, was just 0.35 kcal/mol. The model also reproduces the ab initio geometry and flexibility of Tc. As further tests, we did simulations of a Tc crystal, of Tc:Mg2+ and Tc:Ca2+ complexes in aqueous solution, and of a solvated complex between Tc:Mg2+ and the Tet repressor protein (TetR). With slight, ad hoc adjustments, the model can reproduce the experimental, relative, Tc binding affinities of Mg2+ and Ca2+. It performs well for the structure and fluctuations of the Tc:Mg2+:TetR complex. The model should therefore be suitable to investigate the interactions of Tc with proteins and RNA. It provides a starting point to parameterize other compounds in the large Tc family.

Calcium↗

Deletion of the PB-loop in the L(CM) subunit does not affect phycobilisome assembly or energy transfer functions in the cyanobacterium Synechocystis sp. PCC6714.

In cyanobacteria, light energy is mainly harvested for photosynthesis by the phycobilisome (PBS): a large pigment-protein complex. This complex is composed of heterodimeric phycobiliproteins that are assembled with the aid of linker polypeptides in order to optimize light-energy absorbance and transfer to photosystem II. The core membrane linker subunit (L(CM)) is a fascinating multifunctional polypeptide that participates in the PBS structure, function and anchoring to the photosynthetic membrane. Sequence analysis has defined several domains within the L(CM) polypeptide. The C-terminal portion contains two to four repeated domains that are similar to the conserved domains of linker polypeptides and are believed to play the same role. The N-terminal portion is similar to phycobiliproteins (PB-domain) and carries, like phycobiliproteins, a covalently linked phycobilin chromophore. This domain is interrupted by a so-called PB-loop insertion. The PB-domain of the L(CM) is thus regarded as one of the core subunits, with its PB-loop protruding towards the photosynthetic membrane. The PB-loop was thought to be involved in the attachment of the PBS to the photosynthetic membrane. We generated an apcE gene (encoding L(CM)), in which we deleted the sequence encoding 54 amino acids of the PB-loop domain. The modified gene was expressed in a Synechocystis PCC6714 strain in which the apcE gene had been inactivated. The truncated polypeptide was functionally equivalent to the wild-type L(CM); PBSs were assembled and functioned as in the wild-type. The PB-loop of the L(CM) seems thus dispensable for the PBS biogenesis and function.

Amino Acid Sequence↗

Somatic versus reproductive energy allocation in Papua New Guinea: life history theory and public health policy.

A fundamental evolutionary problem faced by organisms is how to allocate energy to somatic and reproductive functions in ways that optimize fitness. Given that energy is limited in all environments, energy allocation necessarily involves physiological tradeoffs between such factors as growth and reproduction, reproduction and condition, and current reproduction and future survival. Ultimately, the "decisions" that are made about energy allocation among growth, survival, and reproduction determine life history patterns and trajectories of organisms. For humans, knowing how energy allocation to reproduction will likely impact other aspects of the somatic well-being of individuals may also have practical implications for public health policy. This article reviews the evidence for energy tradeoffs between somatic and reproductive functioning in a range of human societies. It also seeks to corroborate the results of earlier work in Papua New Guinea on lactation-related maternal energy depletion using an independent measure of maternal energy reserves, tetrapolar bioelectrical impedance analysis. The current analysis shows that maternal energy reserves decline over the course of lactation and that a cumulative parity-specific decline in maternal energy reserves also exists. A longitudinal follow-up of five women over 11 years shows the decline to amount to about 3 mm of subcutaneous fat per round of pregnancy and lactation. The results corroborate predictions from life history theory and have applied public health implications. In particular, It is suggested that policies such as lactation advocacy that encourage enhanced energy allocation to reproduction in order to promote child health may have the unintended result of compromising maternal well-being, particularly in nations of the developing world. Consequently, it is recommended that nutritional support of mothers be implemented in concert with lactation promotion.

Body Composition↗

Does follicle excision always result in enlargement of offspring size in lizards?

An experimental reduction of offspring number has been reported to result in enlargement of offspring size in lizards. We applied the "follicle excision" technique to a lacertid lizard (Takydromus septentrionalis) to examine whether this effect is generalisable to lizards. Of the 82 females that produced 3 successive clutches in the laboratory, 23 females underwent follicle excision after they oviposited the first clutch. Follicle excision reduced clutch size, but did not alter egg size. This result indicates that egg size is not altered during vitellogenesis in T. septentrionalis. Females undergoing follicle excision produced a third clutch (a second post-surgical clutch) as normally as did control females. Females switched from producing more but smaller eggs early in the breeding season to fewer but larger eggs later in the season. Our results indicate that female T. septentrionalis maximize reproductive success by diverting an optimal, rather than a higher, fraction of the available energy to individual offspring. This optimized allocation of the available energy to offspring production explains why follicle excision does not result in enlargement of egg size in this species. Our study provides evidence that an experimental reduction of offspring number does not always result in enlargement of offspring size in lizards.

Animals↗

How connective tissues temporally process mechanical stimuli.

Connective tissues have the capacity to adapt to a changing mechanical environment. Considerable experimental evidence suggests, however, that tissues respond to only a small portion of mechanical loads they experience and thus ignore the majority of the load they experience. Evidence suggests that tissues 'temporally process' these external mechanical signals in specific ways: 1) they respond in a trigger-like manner after a relatively few events or cycles of loading; 2) they respond only to some window of strain magnitude; 3) they exhibit a refractory period after a response; 4) they have a memory for previous stimuli. These characteristics do not necessarily mirror distinct cellular phenomena but rather reflect typical features of experimental and theoretical models. The manner in which tissues temporally process mechanical signals can be explained by energy transfer over short periods of time from the matrix to the second messenger systems. Much of the energy input into connective tissues during deformation is recovered, and relatively little is 'lost' and thus potentially transferable to the cells. Since evolutionary principles suggest that a pathway of response needs to be defined by biologically optimal use of energy, it is logical that cells would have evolved mechanisms to respond to a small finite level of integrated stimuli in order to rapidly respond (fitness) especially in times of environmental duress.

Adaptation, Physiological↗

Ecological role of energy taxis in microorganisms.

Motile microorganisms rapidly respond to changes in various physico-chemical gradients by directing their motility to more favorable surroundings. Energy generation is one of the most important parameters for the survival of microorganisms in their environment. Therefore it is not surprising that microorganisms are able to monitor changes in the cellular energy generating processes. The signal for this behavioral response, which is called energy taxis, originates within the electron transport system. By coupling energy metabolism and behavior, energy taxis is fine-tuned to the environment a cell finds itself in and allows efficient adaptation to changing conditions that affect cellular energy levels. Thus, energy taxis provides cells with a versatile sensory system that enables them to navigate to niches where energy generation is optimized. This behavior is likely to govern vertical species stratification and the active migration of motile cells in response to shifting gradients of electron donors and/or acceptors which are observed within microbial mats, sediments and soil pores. Energy taxis has been characterized in several species and might be widespread in the microbial world. Genome sequencing revealed that many microorganisms from aquatic and soil environments possess large numbers of chemoreceptors and are likely to be capable of energy taxis. In contrast, species that have a fewer number of chemoreceptors are often found in specific, confined environments, where relatively constant environmental conditions are expected. Future studies focusing on characterizing behavioral responses in species that are adapted to diverse environmental conditions should unravel the molecular mechanisms underlying sensory behavior in general and energy taxis in particular. Such knowledge is critical to a better understanding of the ecological role of energy taxis.

Adaptation, Physiological↗