Weak Hot Spot Research Articles

Categorization of hotspots into three types – weak, moderate and strong to distinguish protein–protein versus protein–peptide interactions

Protein–protein and protein–peptide interactions (PPI and PPepI) belong to a similar category of interactions, yet seemingly subtle differences exist among them. To characterize differences between protein–protein (PP) and protein–peptide (PPep) interactions, we have focussed on two important classes of residues-hotspot and anchor residues. Using implicit solvation-based free energy calculations, a very large-scale alanine scanning has been performed on benchmark datasets, consisting of over 5700 interface residues. The differences in the two categories are more pronounced, if the data were divided into three distinct types, namely – weak hotspots (having binding free energy loss upon Ala mutation, ΔΔG, ∼2–10 kcal/mol), moderate hotspots (ΔΔG, ∼10–20 kcal/mol) and strong hotspots (ΔΔG ≥ ∼20 kcal/mol). The analysis suggests that for PPI, weak hotspots are predominantly populated by polar and hydrophobic residues. The distribution shifts towards charged and polar residues for moderate hotspot and charged residues (principally Arg) are overwhelmingly present in the strong hotspot. On the other hand, in the PPepI dataset, the distribution shifts from predominantly hydrophobic and polar (in the weak type) to almost similar preference for polar, hydrophobic and charged residues (in moderate type) and finally the charged residue (Arg) and Trp are mostly occupied in the strong type. The preferred anchor residues in both categories are Arg, Tyr and Leu, possessing bulky side chain and which also strike a delicate balance between side chain flexibility and rigidity. The present knowledge should aid in effective design of biologics, by augmentation or disruption of PPIs with peptides or peptidomimetics. Communicated by Ramaswamy H. Sarma

Compound super-oscillation lens for reflective confocal imaging

The super-oscillation lens (SOL) can achieve super-resolution focusing but have to trade-off with weaker hotspots and higher sidebands. We propose a single compound SOL to achieve reflective confocal imaging in principle without additional lenses. The designed SOL consists of an outer lens and an inner lens which play the role of focusing lens and collective lens respectively. As a result, focusing and collecting functions can be simultaneously realized. The improved system can achieve excellent imaging performance with an ultra-high resolution (<0.314λ/NA, NA stands for numerical aperture), and almost negligible side lobe ratio and no side bands, which proved superior to conventional laser scanning confocal microscopy and single SOL. This technology can be attractive for a variety of applications in super-resolution imaging and biomedical sciences.

MCNPX simulation and experimental validation of an unmanned aerial radiological system (UARS) for rapid qualitative identification of weak hotspots

Nuclear threats such as dirty bombs and illicit trafficking of radioactive sources are major concerns of humanity. Fast detection and accurate localization of radioactive material out of regulatory control (MORC) by autonomous and semi-autonomous monitoring systems like robots can help to reduce radiation exposure to the public and workers, and it will improve security and peace in the world. This study proposes an autonomous radiological monitoring system consisting of a 2-inch NaI detector coupled to a PM tube and mounted on a multi-rotor UAV to detect radioactive sources. First, an experimental scenario was modeled using the MCNPX Monte Carlo (MC) code. In this modeling, the gamma spectra in 15 detectors were recorded from the rays emitted simultaneously from the areas' sources. The total count under the spectrum was measured for each of the detectors at different heights. The experimental tests were also performed to detect the simultaneous effect of five low-level Co-60 and Cs-137 point sources on a soccer field. Next, the modeling results were compared with the experimental ones, which showed good agreement and the capability to use MC modeling to simulate different radiological scenarios. The experimental results also showed that at 50 cm, all radioactive sources were successfully detected in their actual location. By decreasing the flight height, the ability of the monitoring unmanned aerial to detect radioactive sources was increased significantly.

Improved Upper Bounds for the Hot Spots Constant of Lipschitz Domains

The Hot Spots constant for bounded smooth domains was recently introduced by Steinerberger (2021) as a means to control the global extrema of the first nontrivial eigenfunction of the Neumann Laplacian by its boundary extrema. We generalize the Hot Spots constant to bounded Lipschitz domains and show that it leads to an if and only if condition for the weak Hot Spots conjecture HS2 from Ba\~{n}uelos and Burdzy (1999). We also derive a new general formula for a dimension-dependent upper bound that can be tailored to any specific class of domains. This formula is then used to compute upper bounds for the Hot Spots constant of the class of all bounded Lipschitz domains in $\mathbb{R}^d$ for both small $d$ and for asymptotically large $d$ that significantly improve upon the existing results.

Why Some Targets Benefit from beyond Rule of Five Drugs.

Beyond rule-of-five (bRo5) compounds are increasingly used in drug discovery. Here we analyze 37 target proteins that have bRo5 drugs or clinical candidates. Targets can benefit from bRo5 drugs if they have "complex" hot spot structure with four or more hots spots, including some strong ones. Complex I targets show positive correlation between binding affinity and molecular weight. These targets are conventionally druggable, but reaching additional hot spots enables improved pharmaceutical properties. Complex II targets, mostly protein kinases, also have strong hot spots but show no correlation between affinity and ligand molecular weight, and the primary motivation for creating larger drugs is to increase selectivity. Each target considered as complex III has some specific reason for requiring bRo5 drugs. Finally, targets with "simple" hot spot structure, i.e., three or fewer weak hot spots, must use larger compounds that interact with surfaces beyond the hot spot region to achieve acceptable affinity.

Development of a high sensitivity pinhole type gamma camera using semiconductors for low dose rate fields

We developed a pinhole type gamma camera, using a compact detector module of a pixelated CdTe semiconductor, which has suitable sensitivity and quantitative accuracy for low dose rate fields. In order to improve the sensitivity of the pinhole type semiconductor gamma camera, we adopted three methods: a signal processing method to set the discriminating level lower, a high sensitivity pinhole collimator and a smoothing image filter that improves the efficiency of the source identification. We tested basic performances of the developed gamma camera and carefully examined effects of the three methods. From the sensitivity test, we found that the effective sensitivity was about 21 times higher than that of the gamma camera for high dose rate fields which we had previously developed. We confirmed that the gamma camera had sufficient sensitivity and high quantitative accuracy; for example, a weak hot spot (0.9 μSv/h) around a tree root could be detected within 45 min in a low dose rate field test, and errors of measured dose rates with point sources were less than 7% in a dose rate accuracy test.

The Zeldovich spontaneous reaction wave propagation concept in the fast/modest heating limits

Quantitative mathematical models describe planar, spontaneous, reaction wave propagation (Zeldovich, Combust. Flame, vol. 39, 1980, pp. 211–214) in a finite hot spot volume of reactive gas. The results describe the complete thermomechanical response of the gas to a one-step, high-activation-energy exothermic reaction initiated by a tiny initial temperature non-uniformity in a gas at rest with uniform pressure. Initially, the complete conservation equations, including all transport terms, are non-dimensionalized to identify parameters that quantify the impact of viscosity, conduction and diffusion. The results demonstrate unequivocally that transport terms are tiny relative to all other terms in the equations, given the relevant time and length scales. The asymptotic analyses, based on the reactive Euler equations, describe both induction and post-induction period models for a fast heat release rate (induction time scale short compared to the acoustic time of the spot), as well as a modest heat release rate (induction time scale equivalent to the acoustic time). Analytical results are obtained for the fast heating rate problem and emphasize the physics of near constant-volume heating during the induction period. Weak hot spot expansion is the source of fluid expelled from the original finite volume and is a ‘piston-effect’ source of acoustic mechanical disturbances beyond the spot. The post-induction period is characterized by the explosive appearance of an ephemeral, spatially uniform high-temperature, high-pressure spot embedded in a cold, low-pressure environment. In analogy with a shock tube the subsequent expansion process occurs on the acoustic time scale of the spot and will be the source of shocks propagating beyond the spot. The modest heating rate induction period is characterized by weakly compressible phenomena that can be described by a novel system of linear wave equations for the temperature, pressure and induced velocity perturbations driven by nonlinear chemical heating, which provides physical insights difficult to obtain from the more familiar ‘Clarke equation’. When the heating rate is modest, reaction terms in the post-induction period Euler equations exhibit a form of singular behaviour in the high-activation-energy limit, implying the need to use a nonlinear exponential scaling for time and space, developed originally to describe spatially uniform thermal explosions (Kassoy, Q. J. Mech. Appl. Maths, vol. 30, 1977, pp. 71–89). Here again the result will be the explosive appearance of an ephemeral spatially uniform high-temperature, high-pressure hot spot. These results demonstrate that an initially weak temperature non-uniformity in a finite hot spot can be the source of acoustic and shock wave mechanical disturbances in the gas beyond the spot that may be related to rocket engine instability and engine knock.

Lithium Distribution in Monocrystalline Silicon-Based Lithium-Ion Batteries

There is a growing demand on power sources for micro-system applications. Li-ion micro batteries (µ-batteries) with silicon-based anodes may fulfill the necessary requirements. Silicon shows superior properties as anode material in batteries such as a very high specific capacity [1]. Well-engineered manufacturing techniques allow a high level of integration into silicon-based semiconductor devices [2].One challenging topic for the integration concerns lithium distribution inside the anode to understand the cyclability of silicon. Moreover, the prevention of loss of Li-ion in non-active areas of the battery is a key issue. Therefore, the introduction of a tight barrier layer is essential for such systems [3]. For these investigations analytical techniques are required, which can obtain information on the lateral as well as depth lithium distribution.Surface structured silicon and sputtered diffusion barriers on silicon were tested as working electrodes in a half-cell Swagelok® design together with a EC: EMC, LiPF6-based electrolyte. Two mass spectrometry based techniques were applied to investigate the properties of structured silicon anodes together with the barrier characteristics of refectory metal materials: (i) ToF-SIMS was used as imaging technique for depth profiling the first micrometers and (ii) Laser ablation ICP-MS allowed to measure depth-profiles of up to hundreds of microns perfectly complementing the ToF-SIMS technique.The presented study focuses on the non-uniform Li-distribution in silicon anodes with the aim to avoid structural weak hotspots due to locally unbalanced dilatation. Beside the detailed investigation of the native anode structures we tested different silicon-barrier combinations, e.g., Si – TiN, to clarify their potential as Li-inert material in future battery applications (see Fig. 1). Acknowledgement Financial support by the Federal Ministry of Economy, Family and Youth and the National Foundation for Research, Technology and Development is gratefully acknowledged. Moreover, we thank Infineon Technology Austria AG for financial and technical support.

Building of the Amsterdam-Saint Paul plateau: A 10 Myr history of a ridge-hot spot interaction and variations in the strength of the hot spot source

The Amsterdam-Saint Paul plateau results from a 10 Myr interaction between the South East Indian Ridge and the Amsterdam-Saint Paul hot spot. During this period of time, the structure of the plateau changed as a consequence of changes in both the ridge-hot spot relative distance and in the strength of the hot spot source. The joint analysis of gravity-derived crust thickness and bathymetry reveals that the plateau started to form at ~10 Ma by an increase of the crustal production at the ridge axis, due to the nearby hot spot. This phase, which lasted 3-4 Myr, corresponds to a period of a strong hot spot source, maybe due to a high temperature or material flux, and decreasing ridge-hot spot distance. A second phase, between ~6 and ~3 Ma, corresponds to a decrease in the ridge crustal production. During this period, the hot spot center was close to the ridge axis and this reduced magmatic activity suggests a weak hot spot source. At ~3 Ma, the ridge was located approximately above the hot spot center. An increase in the hot spot source strength then resulted in the building of the shallower part of the plateau. The variations of the melt production at the ridge axis through time resulted in variations in crustal thickness but also in changes in the ridge morphology. The two periods of increased melt production correspond to smooth ridge morphology, characterized by axial highs, while the intermediate period corresponds to a rougher, rift-valley morphology. These variations reveal changes in axial thermal structure due to higher melting production rates and temperatures.

Binding Hot Spots and Amantadine Orientation in the Influenza A Virus M2 Proton Channel

Structures of truncated versions of the influenza A virus M2 proton channel have been determined recently by x-ray crystallography in the open conformation of the channel, and by NMR in the closed state. The structures differ in the position of the bound inhibitors. The x-ray structure shows a single amantadine molecule in the middle of the channel, whereas in the NMR structure four drug molecules bind at the channel's outer surface. To study this controversy we applied computational solvent mapping, a technique developed for the identification of the most druggable binding hot spots of proteins. The method moves molecular probes—small organic molecules containing various functional groups—around the protein surface, finds favorable positions using empirical free energy functions, clusters the conformations, and ranks the clusters on the basis of the average free energy. The results of the mapping show that in both structures the primary hot spot is an internal cavity overlapping the amantadine binding site seen in the x-ray structure. However, both structures also have weaker hot spots at the exterior locations that bind rimantadine in the NMR structure, although these sites are partially due to the favorable interactions with the interfacial region of the lipid bilayer. As confirmed by docking calculations, the open channel binds amantadine at the more favorable internal site, in good agreement with the x-ray structure. In contrast, the NMR structure is based on a peptide/micelle construct that is able to accommodate the small molecular probes used for the mapping, but has a too narrow pore for the rimantadine to access the internal hot spot, and hence the drug can bind only at the exterior sites.

Population genomic inference of recombination rates and hotspots

As more human genomic data become available, fine-scale recombination rate variation can be inferred on a genome-wide scale. Current statistical methods to infer recombination rates that can be applied to moderate, or large, genomic regions are limited to approximated likelihoods. Here, we develop a Bayesian full-likelihood method using Markov Chain Monte Carlo (MCMC) to estimate background recombination rates and hotspots. The probability model is inspired by the observed patterns of recombination at several genomic regions analyzed in sperm-typing studies. Posterior probabilities and Bayes factors of recombination hotspots along chromosomes are inferred. For moderate-size genomic regions (e.g., with <100 SNPs), the full-likelihood method is used. Larger regions are split into subintervals (typically each having between 20 and 50 markers). The likelihood is approximated based on the genealogies for each subinterval. The background recombination rates, hotspots, and parameters are evaluated by using a parallel computing approach and assuming shared parameters across the subintervals. Simulation analyses show that our method can accurately estimate the variation in recombination rates across genomic regions. In particular, clusters of hotspots can be distinguished even though weaker hotspots are present. The method is applied to SNP data from the HLA region, the MS32, and chromosome 19.

PKD2 mutations in a Czech population with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous and caused by mutations in at least three different loci. Based on linkage analysis, mutations in the PKD2 gene are responsible for approximately 15% of the cases. PKD2-linked ADPKD is supposed to be a milder form of the disease, its mean age of end-stage renal failure (ESRF) approximately 20 years later than PKD1. We screened all coding sequences of the PKD2 gene in 115 Czech patients. From dialysis centres in the Czech Republic and from the Department of Nephrology of the General Hospital in Prague, we selected 52 patients (29 males, 23 females), who reached ESRF after the age of 63, and 10 patients (three males, seven females) who were not on renal replacement therapy at that age. The age of 63 was used as the cut-off because it is between the recently published ages of onset of ESRF for PKD1 and PKD2. From PKD families we also selected 53 patients (26 males, 27 females) who could be linked to either the PKD1 or PKD2 genes by linkage analysis. An affected member from each family was analysed by heteroduplex analysis (HA) for all 15 coding regions. Samples exhibiting shifted bands on gels were sequenced. We detected 22 mutations (six new mutations)-14 mutations in 62 patients (23%) with mild clinical manifestations, eight in 53 families (15%) with possible linkage to both PKD genes. As the detection rate of HA is approximately 70-80%, we estimate the prevalence of PKD2 cases in the Czech ADPKD population to be 18-20%. We identified nonsense mutations in eight patients (36.5%), frameshifting mutations in 12 patients (54.5%) and missense mutations in two patients (9%). In this study in the Czech population we identified 22 mutations (six of which were new mutations). The prevalence of PKD2 cases was 18-20% and the mean age of ESRF was 68.3 years. An at-least weak hot spot in exon 1 of the PKD2 gene was found.

Stable propagation and all-optical switching in planar waveguide–antiwaveguide periodic structures

A planar periodic nonlinear structure composed of alternating waveguiding (WG) and antiwaveguiding (AWG) sections is considered. Detailed simulations demonstrate that fairly long stable propagation of a beam in this structure is achieved when the lengths of the AWG and WG sections are equal, i.e., both ∼25 wavelengths. Another interesting result is that the stable-propagation length is much larger in both a uniform AWG and in the alternate structure if the input has a Gaussian transverse profile rather than a specially prepared shape that corresponds to the eigenmode of the (anti)waveguide. It is demonstrated that an efficient all-optical switching scheme, controlled by a weak hot spot, which is created by a laser beam shone normally to the structure and focused off axis near the end of any AWG section, can readily be realized in the alternate waveguide.

Temporal and geochemical variability of volcanic products of the Marquesas Hotspot

The Marquesas archipelago is a short, NW‐SE trending cluster of islands and seamounts that formed as a result of volcanic activity over a weak hotspot. This volcanic chain lies at the northern margin of a broad region of warm and compositionally diverse mantle that melts to build several other subparallel volcanic lineaments. Basalts dredged from submerged portions of volcanoes along the Marquesas lineament decrease in age from northwest to southeast. The new sample age distribution yields a volcanic migration rate significantly slower than that expected for Pacific plate motion over a stationary Marquesas hotspot. This and the aberrant orientation of the chain indicate deflection of the plume by westward upper mantle flow. The interaction of this weak plume with upper mantle flow accounts for the temporal and spatial patterns in Marquesan volcanism. The compositions of subaerial and submarine basalts reflect the mixing of at least two mantle sources, distinguished by Sr, Nd, and Pb isotope and trace element compositions. There is a consistent evolutionary pattern at each volcano, from early tholeiitic to later alkalic basalt eruptions. Tholeiitic and transitional lava compositions can be derived by variable degrees of partial melting of a source composed of depleted mid‐ocean ridge basalt mantle (DMM) and mantle characterized by radiogenic Pb (HIMU). Alkalic lava compositions appear to be dominantly the result of smaller degrees of melting of a more radiogenic mantle source (EM II). Large‐scale melting of the lower lithosphere or upper mantle (DMM+HIMU) entrained within a sheared, thermally buoyant plume (EM II) could produce the tholeiitic and transitional basalts found in the main shields of the volcanoes, while alkalic basalts could result from melting of mantle of EM II composition at the edges of the hotspot.