Set Of Analogues Research Articles

Digital-analog quantum learning on Rydberg atom arrays

Abstract We propose hybrid digital-analog learning algorithms on Rydberg atom arrays, combining the potentially practical utility and near-term realizability of quantum learning with the rapidly scaling architectures of neutral atoms. Our construction requires only single-qubit operations in the digital setting and global driving according to the Rydberg Hamiltonian in the analog setting. We perform a comprehensive numerical study of our algorithm on both classical and quantum data, given respectively by handwritten digit classification and unsupervised quantum phase boundary learning. We show in the two representative problems that digital-analog learning is not only feasible in the near term, but also requires shorter circuit depths and is more robust to realistic error models as compared to digital learning schemes. Our results suggest that digital-analog learning opens a promising path towards improved variational quantum learning experiments in the near term.

The tectonic implications of a rare metamorphic event in eastern China during the Earth's “middle age”

The Mesoproterozoic Era has long been considered a relatively stable, silent, and even "boring" period in Earth's history, during which the lithosphere was tectonically inactive. However, an increasing amount of evidence suggests that metamorphism and magmatism were much more widespread and intense than previously thought, implying that this period was dynamic. Here we report metamorphism around ca. 1.4 Ga along the southeastern margin of the North China Craton, eastern China. We conduct TIMA, EMPA, and zircon SHRIMP and LA-ICP-MS U-Pb dating on garnet amphibolites and their country rocks. The detailed mineral composition of a representive garnet amphibolite sample is identified and determined by TIMA. Phase equilibria modelling using pseudosections combined with EMPA data indicates the peak metamorphism stage (M 2 ) of the garnet amphibolites at a P-T condition of 10.6-11.2 kbar/820 ℃. SHRIMP Zircon U-Pb analysis yields an age of 1366 ± 17 Ma for the garnet amphibolites, which is slightly younger than that of its country rock schist (1376 ± 22 Ma). Integrating the metamorphic event with geochemical signatures, magmatic records, and sedimentation patterns in analogous geological settings on other continents, our findings collectively demonstrate a protracted and pervasive orogenic process along the periphery of the Columbia supercontinent.

Synchronization of Gold sequences based on fast transform in a truncated basis of Walsh–Hadamard functions

Based on the analysis of the structures of isomorphic multiplicative groups of extended Galois fields, it is established that any cyclic shift of a pseudo-random Gold sequence can be transformed into a function belonging to the complete set of analogues of Rademacher functions of the corresponding dimension. This made it possible to develop a new algorithm for fast synchronization of Gold sequences based on the calculation of their discrete convolution using fast spectral transformation in a truncated basis of Walsh–Hadamard functions. The gain of the developed algorithm in terms of the number of arithmetic operations compared to the traditional method of calculating discrete convolution increases with increasing sequence length N and for N=511.1023 is approximately 3.4 times.

Modified (2′-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway

Autophagy is a conserved self-digestion process, which governs regulated degradation of cellular components. Autophagy is upregulated upon energy shortage sensed by AMP-dependent protein kinase (AMPK). Autophagy activators might be contemplated as therapies for metabolic neurodegenerative diseases and obesity, as well as cancer, considering tumor-suppressive functions of autophagy. Among them, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), a nucleoside precursor of the active phosphorylated AMP analog, is the most commonly used pharmacological modulator of AMPK activity, despite its multiple reported “off-target” effects. Here, we assessed the autophagy/mitophagy activation ability of a small set of (2′-deoxy)adenosine derivatives and analogs using a fluorescent reporter assay and immunoblotting analysis. The first two leader compounds, 7,8-dihydro-8-oxo-2′-deoxyadenosine and -adenosine, are nucleoside forms of major oxidative DNA and RNA lesions. The third, a derivative of inactive N6-methyladenosine with a metabolizable phosphate-masking group, exhibited the highest activity in the series. These compounds primarily contributed to the activation of AMPK and outperformed AICAr; however, retaining the activity in knockout cell lines for AMPK (ΔAMPK) and its upstream regulator SIRT1 (ΔSIRT1) suggests that AMPK is not a main cellular target. Overall, we confirmed the prospects of searching for autophagy activators among (2′-deoxy)adenosine derivatives and demonstrated the applicability of the phosphate-masking strategy for increasing their efficacy.

Discovery of Substituted 5-(2-Hydroxybenzoyl)-2-Pyridone Analogues as Inhibitors of the Human Caf1/CNOT7 Ribonuclease.

The Caf1/CNOT7 nuclease is a catalytic component of the Ccr4-Not deadenylase complex, which is a key regulator of post-transcriptional gene regulation. In addition to providing catalytic activity, Caf1/CNOT7 and its paralogue Caf1/CNOT8 also contribute a structural function by mediating interactions between the large, non-catalytic subunit CNOT1, which forms the backbone of the Ccr4-Not complex and the second nuclease subunit Ccr4 (CNOT6/CNOT6L). To facilitate investigations into the role of Caf1/CNOT7 in gene regulation, we aimed to discover and develop non-nucleoside inhibitors of the enzyme. Here, we disclose that the tri-substituted 2-pyridone compound 5-(5-bromo-2-hydroxy-benzoyl)-1-(4-chloro-2-methoxy-5-methyl-phenyl)-2-oxo-pyridine-3-carbonitrile is an inhibitor of the Caf1/CNOT7 nuclease. Using a fluorescence-based nuclease assay, the activity of 16 structural analogues was determined, which predominantly explored substituents on the 1-phenyl group. While no compound with higher potency was identified among this set of structural analogues, the lowest potency was observed with the analogue lacking substituents on the 1-phenyl group. This indicates that substituents on the 1-phenyl group contribute significantly to binding. To identify possible binding modes of the inhibitors, molecular docking was carried out. This analysis suggested that the binding modes of the five most potent inhibitors may display similar conformations upon binding active site residues. Possible interactions include π-π interactions with His225, hydrogen bonding with the backbone of Phe43 and Van der Waals interactions with His225, Leu209, Leu112 and Leu115.

Regiospecific Coelenterazine Analogs for Bioassays and Molecular Imaging.

Bioluminescence (BL) generated by luciferase-coelenterazine (CTZ) reactions is broadly employed as an optical readout in bioassays and in vivo molecular imaging. In this study, we demonstrate a systematic approach to elucidate the luciferase-CTZ binding chemistry with a full set of regioisomeric CTZ analogs, where all the functional groups were regiochemically modified. When the chemical structures were categorized into Groups 1-6, the even-numbered Groups (2, 4, and 6) of the CTZ analogs are found to be exceptionally bright with NanoLuc enzyme. A CTZ analogue M2 was the brightest with NanoLuc and the reason was deciphered by a computational analysis of the binding modes. We also report that (i) the regioisomeric CTZ analogs collectively create unique intensity patterns according to each marine luciferase, (ii) the quantitative structure-activity relationship analysis revealed the roles of respective functional groups of CTZ analogs, and (iii) the regioisomeric CTZ analogs also exert red shifts of the BL spectra and color variation: that is, the λmax values are near 500 nm with NanoLuc, near 530 nm with ALuc16, and near 570 nm with RLuc86SG. The advantages of the regioisomeric CTZ analogs were finally demonstrated using (i) a dual-luciferase system with M2-specific NanoLuc and native CTZ-specific ALuc16, (ii) an estrogen activatable single-chain BL probe by imaging, and (iii) BL imaging of live mice bearing tumors expressing NanoLuc and RLuc8.6SG. This study is the first systematic approach to elucidate the regiochemistry in BL imaging studies. This study provides new insights into how CTZ analogs regiochemically work in BL reporter systems and guides the specific applications to molecular imaging.

Why does the Milky Way have a bar?

ABSTRACT There is no doubt that the Milky Way is a barred galaxy; however, factors that establish its prominent morphology remain largely elusive. In this work, we attempt to constrain the history of the MW by tracing the present-day parameters and evolution of a set of MW and M31 analogues from the TNG50 simulations. We find that the strength of bars at $z=0$ correlates well not only with the stellar mass build-up but also, more crucially, with the time of onset of stellar discs. Discs of strongly barred galaxies form early ($z \gtrsim 2-3$), compared to weakly and non-barred galaxies ($z \approx 1-1.5$). Although we are cautious to draw ultimate conclusions about the governing factor of discs formation due to the complexity and correlations between different phenomena, the observed morphological diversity can be tentatively explained by a substantial variation in the gas angular momentum around proto-galaxies already at $z\approx 3-5$; in such a way, early discs formed from gas with larger angular momentum. By comparing the formation time-scales of discs of barred galaxies in the TNG50 sample, we infer that the MW has a strong bar ($0.35\lt A_2\lt 0.6$), and that its stellar disc started to dominate over the spheroidal component already at $z \approx 2$, with a mass of $\approx 1 \pm 0.5 \times 10^{10} M_\odot$. We conclude that the presence of a strong bar in the MW is a natural manifestation of the early formation of the stellar disc, which made possible bursty but highly efficient star formation at high redshift.

Growth, yield and quality response of Eggplant (Solanum melongena L.) to blended NPSB fertilizer rates and intra-row spacing in Boloso Bombe district, Wolaita zone, South Ethiopia

Eggplant is the most important fruit vegetable crop in many countries, including Ethiopia. In spite of this, its production is hindered by low nutrient availability in soil and suboptimal intra-row spacing. In order to address these issues, a field investigation took place in the Wolaita zone during 2022/23 growing season to evaluate the effects of various concentrations of blended NPSB fertilizer and intra-row spacing on the growth, yield, and quality of eggplants. Five various blended NPSB fertilizer rates (0, 50, 100, 150, and 200 kg ha−1) and three intra-row spacing distances (30, 40, and 50 cm) were used in the investigation, which was designed as a randomized complete block with three replicates. Based on an analysis of variance, it was discovered that the main effects of NPSB fertilizer rates and intra-row spacing significantly (p < 0.01) affected many of parameters, including dry matter content, total soluble solids, fruit number, fruit length, and days to 50 % flowering. Additionally, the interaction effect between NPSB fertilizer and intra-row spacing significantly (p < 0.05) impacted the number of days to first fruit harvest, plant height, leaf area, branch number, leaf number, fruit diameter, fresh fruit yield, marketable fresh fruit yield, unmarketable fresh fruit yield, and total fresh fruit yield. According to the current investigation, the highest marketable fresh fruit yield (121.04 t ha−1) was obtained by 150 kg ha−1 NPSB with 40 cm intra-row spacing. These findings suggest that 150 kg ha−1 of blended NPSB fertilizer with 40 cm distance between plant spacing is optimal for eggplant cultivation in the study area and analogous agro-ecological settings. This optimized approach can effectively support eggplant growers in maximizing both yield and quality outcomes.

Comparing Rover and Helicopter Planetary Mission Architectures in a Mars Analog Setting in Iceland

The Rover–Aerial Vehicle Exploration Network project field-tested planetary mission operations within a Mars analog environment in Iceland using stand-alone rover and helicopter architectures. Mission planning, implementation, and results are reported for the rover mission and briefly summarized for the helicopter mission. The outcomes of both missions are subsequently compared. Field implementation occurred from 2022 July to August at the Holuhraun lava flow. The rover science operations team executed a 14 sol (Martian day) mission that achieved mission, science, and sampling goals, including the contextualization, acquisition, and planned caching of two eolian and two rock samples. The helicopter science operations team executed a plan of comparable length but emphasized different science goals given long-range flight capabilities and landing limitations. The resolution and targetability of the rover payload enabled more detailed analyses, whereas the helicopter was better able to map flow-scale morphologies. The rover’s exploration was limited by daily mobility duration limits and hazardous terrain, whereas the helicopter’s exploration was constrained by landing site hazards. Resource limitations resulted from lengthier rover drives and data-volume-intensive helicopter imaging surveys. Future missions using combined rover–helicopter architectures should account for each spacecraft’s resource needs and acknowledge system strengths in different geologic settings. Both missions served to establish operations strategies and mission outcomes to be applied to future combined rover and helicopter mission architectures, while the helicopter mission also evaluated strategies and outcomes for future stand-alone airborne missions. Findings in this work are relevant to future missions seeking to optimize strategies for planetary mission operations.

Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity.

The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy-directed ruthenium catalyzed trans-hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non-natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of any noticeable cytotoxicity. The "northern" allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.

Tales of twin cities: what are climate analogues good for?

This article provides an epistemological assessment of climate analogue methods, with specific reference to the use of spatial analogues in the study of the future climate of target locations. Our contention is that, due to formal and conceptual inadequacies of geometrical dissimilarity metrics and the loss of relevant information, especially when reasoning from the physical to the socio-economical level, purported inferences from climate analogues of the spatial kind we consider here prove limited in a number of ways. Indeed, we formulate five outstanding problems concerning the search for best analogues, which we call the problem of non-uniqueness of the source, problem of non-uniqueness of the target, problem of average, problem of non-causal correlations and problem of inferred properties, respectively. In the face of such problems, we then offer two positive recommendations for a fruitful application of this methodology to the assessment of impact, adaptation and vulnerability studies of climate change, especially in the context of what we may prosaically dub “twin cities”. Arguably, such recommendations help decision-makers constrain the set of plausible climate analogues by integrating local knowledge relevant to the locations of interest.

Not all shell beds are made equal: Recognizing singular event‐concentrations in megalakes

ABSTRACTEvent deposition accounts for a large part of the preserved sedimentary record. Tempestites, tsunamites and turbidites are among the most common event deposits in marine and lacustrine systems. While facies models exist for these deposits, the challenge lies in the fact that diverse triggers can give rise to analogous depositional processes and comparable taphonomic features, making it difficult to pinpoint the precise trigger for an event bed. Hence, five distinct modern‐type shell concentrations are studied in Permian strata from the Paraná Basin, West Gondwana, to access the parameters to discriminate event phenomena, and their associated depositional and taphonomic processes. During this time interval, the basin underwent continuous continentalization due to orogenic events, leading to the entrapment of epeiric marine waters and the transformation of the system into a megalake, supporting a diverse and endemic freshwater bivalve fauna. While sedimentation was primarily influenced by meteorological events, certain stratigraphic intervals were also affected by tectonically active periods and meteor impact events. The different products are categorized into bioclastic sandstone, shell bed, shell‐rich phosclast rudstone and shell‐rich conglomerate that are interpreted as proximal and distal tempestites and tsunamites, respectively. Finally, the products and the processes that lead to the deposition of tempestites and tsunamites are compared to establish diagnostic signatures that may be applied to differentiate these event concentrations in analogous settings from the geological record.

The molecular determinants of calcium ATPase inhibition by curcuminoids

The natural product curcumin and some of its analogs are known inhibitors of the transmembrane enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). Despite their widespread use, the curcuminoids' binding site in SERCA and their relevant interactions with the enzyme remain elusive. This lack of knowledge has prevented the development of curcuminoids into valuable experimental tools or into agents of therapeutic value. We used the crystal structures of SERCA in its E1 conformation in conjunction with computational tools such as docking and surface screens to determine the most likely curcumin binding site, along with key enzyme/inhibitor interactions. Additionally, we determined the inhibitory potencies and binding affinities for a small set of curcumin analogs. The predicted curcumin binding site is a narrow cleft in the transmembrane section of SERCA, close to the transmembrane/cytosol interface. In addition to pronounced complementarity in shape and hydrophobicity profiles between curcumin and the binding pocket, several hydrogen bonds were observed that were spread over the entire curcumin scaffold, involving residues on several transmembrane helices. Docking-predicted interactions were compatible with experimental observations for inhibitory potencies and binding affinities. Based on these findings, we propose an inhibition mechanism that assumes that the presence of a curcuminoid in the binding site arrests the catalytic cycle of SERCA by preventing it from converting from the E1 to the E2 conformation. This blockage of conformational change is accomplished by a combination of steric hinderance and hydrogen-bond-based cross-linking of transmembrane helices that require flexibility throughout the catalytic cycle.

Development of phenyl-urea-based small molecules that target penicillin-binding protein 4.

Staphylococcus aureus has the ability to invade cortical bone osteocyte lacuno-canalicular networks (OLCNs) and cause osteomyelitis. It was recently established that the cell wall transpeptidase, penicillin-binding protein 4 (PBP4), is crucial for this function, with pbp4 deletion strains unable to invade OLCNs and cause bone pathogenesis in a murine model of S. aureus osteomyelitis. Moreover, PBP4 has recently been found to modulate S. aureus resistance to β-lactam antibiotics. As such, small molecule inhibitors of S. aureus PBP4 may represent dual functional antimicrobial agents that limit osteomyelitis and/or reverse antibiotic resistance. A high throughput screen recently revealed that the phenyl-urea 1 targets PBP4. Herein, we describe a structure-activity relationship (SAR) study on 1. Leveraging in silico docking and modeling, a set of analogs was synthesized and assessed for PBP4 inhibitory activities. Results revealed a preliminary SAR and identified lead compounds with enhanced binding to PBP4, more potent antibiotic resistance reversal, and diminished PBP4 cell wall transpeptidase activity in comparison to 1.

A remarkable change in inhibition potency and selectivity of isofagomine by simple N-modification

AbstractHerein, we present an alternative and elegant synthetic approach toward powerful β-glucosidase inhibitor isofagomine. Derivatizations of the ring nitrogen provided a selected set of N-modified isofagomine analogues. Biological evaluation of these compounds showed a remarkable change in potency as well as α/β-preference for various glycosidases from different sources when compared to the parent compound isofagomine. Overall, the conducted N-modification improved the potency against α-glucosidase from Saccharomyces cerevisiae (GH13). Coming along, significant diminished activities toward GH1 family β-glucosidases from three different sources have been observed for all tested derivatives. Moreover, and contrary to isofagomine, deactivations of β-galactosidase from Escherichia coli (GH2) as well as α-mannosidase from Canavalia ensiformis (GH38) have not been verified for this series of compounds. Graphical abstract

Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective

As a key mediator of chronic pain, neurotrophin nerve growth factor (NGF) binds to two neurotrophin receptors: p75 neurotrophin receptor (p75NTR) and tyrosine kinase receptor A (TrkA). The formation of the p75NTR-NGF-TrkA complex is implicated in the potentiation of chronic pain signals, making it an attractive target for therapeutic explorations. NGF analogues and monoclonal antibodies (mAbs) targeting NGF represent two distinct approaches in modulating the intricate signaling pathways involved in pain transduction mediated by the p75NTR-NGF-TrkA complex. While NGF analogues offer the advantage of tailored design to fine-tune neurotrophic responses, monoclonal antibodies provide a more systemic and comprehensive blockade of NGF, inhibiting its interactions with both p75NTR and TrkA receptors. However, the use of mAbs may pose challenges related to potential side effects and interference with the physiological functions of NGF. As a result, balancing the benefits and drawbacks of the two approaches is critical for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain. In this study, therefore, a novel structural and biophysical approach was employed for the design of NGF analogues to suppress p75NTR-NGF-TrkA-related chronic pain signaling. Employing high-throughput structural modeling and biophysics-based intermolecular binding affinity calculations, this article for the first time puts forward a set of NGF analogues, including in particular NGF analogues with four site-specific mutations, for whose dimerizations the Kd at 37 ◦C were reduced by three orders of magnitude (from 10-9 M to 10-6 M) compared to the Kd at 37 ◦C for the dimerization of native NGFs. Overall, the integration of structural and biophysical perspectives enhances our understanding of the rational design of NGF analogues as promising candidates for the development of NGF-targeted analgesic therapies, which balances the benefits and drawbacks of anti-NGF antibodies and NGF analogues for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain.

Alkyl Lipid Distributions and Compound‐Specific 14C Isotope Compositions in Diverse Sedimentary Archives in Sub‐Antarctic South Georgia: Deconvolving (Past and Present) Marine and Terrestrial Sources and Revealing Localized Export Dynamics in Response to Environmental Change

AbstractAlkyl lipid distributions in terrestrial, lacustrine and marine sedimentary archives on sub‐Antarctic South Georgia are investigated to identify source endmembers and evaluate their variation in response to Holocene environmental changes. To understand organic matter exchange processes along the land‐ocean continuum, we combine lipid compositional data with compound‐specific 14C data in representative sedimentary records. These data provide additional source information and temporal constraints on exchange processes that operate at the landscape level. The alkane, alkanoic acid and alkanol distributions are distinct between terrestrial and marine sources, between vascular and primarily non‐vascular plants, and according to the level of degradation. Compound‐specific 14C ages of alkanes, alkanoic acids and alkanols reveal the complexity of the carbon pools associated with these carbon sources. We find that terrigenous compounds in lacustrine and marine sediments are generally older than those produced by aquatic sources, reflecting intermediate storage in peat/soil prior to deposition. Nonetheless, the pre‐depositional age of terrigenous alkyl lipids differs in the different settings although they are located in close proximity under the same climatic conditions. Overall, the 14C data reflect changes in the balance of accumulation and erosion of organic matter in the terrestrial catchments of the investigated sites in response to prevailing environmental conditions. Petrogenic OC ranges from 0% to 7% and 4%–37% in catchments with minor glacier presence and to up to 67%–76% in the large tidewater glacier catchment. Long‐term biospheric OC turnover seems to have been remarkably constant throughout most of the Holocene and higher than in analog settings in the northern hemisphere.

Design and Characterization of the Engineering Model of the Spectrometer Onboard LuSEE‐Night

AbstractThe Lunar Surface Electromagnetics Explorer—Night, LuSEE‐Night, is a low‐frequency radio astronomy experiment that will explore the cosmic Dark Ages signal on the radio‐quiet farside of the Moon. The LuSEE‐Night carries a radio frequency spectrometer consisting of a set of antennas, analog and digital processing electronics, and will be launched by NASA's Commercial Lunar Payload Services in 2025. The spectrometer is designed to observe the spectrum of the radio sky in the 0.5−50 MHz band. The engineering model (EM) of the four‐channel spectrometer has been developed. The EM has been characterized for linearity, gain, noise, and their temperature dependence, confirming that the EM meets all the requirements for LuSEE‐Night. Three mitigation techniques have been implemented and verified to suppress self‐induced electromagnetic interference. The flight model of the spectrometer is currently being developed and is scheduled to be shipped to the integration site in early 2024.

Conversion Factors for Physical Property Measurements in different Rest Frames Using a Revised Version of Relativity Theory Based on the Uniform Scaling Method

The history of the development of the Uniform Scaling Method is reviewed. It has its beginning with the Law of Causality and Newton’s First Law of Kinetics (Law of Inertia). On this basis it can be concluded that the rates of clocks do not change spontaneously, i.e. without the application of some external force. Since the ratio Q of the rates of any two such (inertial) clocks must therefore itself be a constant, it follows that whenever they are used to measure a specific time difference between two events, their respective results must always be in the same ratio: Δt’=Δt/Q. This relationship is referred to as Newtonian Simultaneity since it guarantees that if one of the clocks finds that the events occurred simultaneously (Δt’=0), the other must do so as well (Δt=0). A useful way to interpret Q is as a conversion factor between the different units of time employed in the two rest frames. If we assume that the value of the speed of light is the same in both rest frames, it follows that they must agree on the unit of speed, i.e. the conversion factor in this case is unity (Q0 ). It therefore follows that the conversion factor for the unit of distance must be exactly the same as that for time, namely also Q. This claim of the Uniform Scaling Method is thus seen to be in direct contradiction to the length contraction tenet of Einstein’s theory of relativity introduced in 1905. Experiments with accelerated electrons carried out by Bucherer in 1909 indicate that their inertial mass increase in direct proportion to γ (v) = (1-v2 c-2)-0.5 (v is the speed of the electrons and c = 299792458 ms-1 is the speed of light in free space), the same ratio as observed for the periods of atomic lines by Ives and Stilwell in 1938. Consistency therefore requires that the conversion factor for inertial mass is the same (Q) as for time. Since inertial mass, time and distance are the three fundamental quantities on which all other physical properties are defined (mks system), it follows that the conversion factor for any other property must be an integral multiple of Q. An analogous set of definitions can also be justified for the corresponding conversion factors in the same two rest frames caused by gravitational effects. In this case the conversion factors are always integral multiples of the quantity S, which therefore plays as analogous role as Q in kinetic scaling. Since experiments with circumnavigating atomic clocks carried out in 1971 by Hafele and Keating found that the two types of effects are completely independent of one another, it is therefore useful to define a product Z of the corresponding Q and S factors for each physical property, including those that are used to define the results of electromagnetic measurements. These total conversion factors are stored in Tables 1 and 2 of the manuscript. They are shown to guarantee that if a physical law is valid in one of the rest frames, it will also hold in the other. This relationship allows for an Addendum to Galileo’s Relativity Principle: The laws of physics are the same in all inertial rest frames, but the units in which their results are expressed can differ from one rest frame to another.

Modulation of proteasome subunit selectivity of syringolins

Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure–activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure–activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding β5 and β2 subunits.