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Cefprozil, an oral second-generation semi-synthetic cephalosporin, possesses a broad spectrum of antimicrobial activity. A granule formulation has been developed to improve medication adherence of the patients. This study was conducted to assess the bioequivalence of the granule formulation to a dry suspension in healthy Chinese volunteers and estimate the pharmacokinetic (PK) profiles of cefprozil. An open-label, randomized, single-dose, two-period, two-group, crossover study was conducted in 60 healthy Chinese volunteers under fasted or fed conditions (30 volunteers for each condition) to assess the bioequivalence between two formulations of cefprozil. Blood samples were collected at specified time intervals, and the plasma concentrations of cis- and trans-cefprozil were determined by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events (AEs) were also recorded. Under fasted conditions, the mean Cmax was (3534.70 ± 634.67) ng/ml, Tmax was (0.98 ± 0.25) h, t1/2 was (1.37 ± 0.13) h and AUC0-t was (9302.86 ± 1618.39) ng·h/ml, respectively, after a single dose of 125 mg cefprozil for suspension. Under fed conditions, the mean Cmax was (2438.80 ± 493.78) ng/ml, Tmax was (1.66 ± 0.76) h, t1/2 was (1.36 ± 0.24) h and AUC0-t was (9332.36 ± 1373.61) ng·h/ml, respectively. The PK parameters of the granule formulation of cefprozil were similar to those of the suspension. The 90% CI values of the GMRs of Cmax, AUC0-t and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence range (80.00–125.00%). According to the criteria for bioequivalence, the test granule formulations of cefprozil and "Cefprozil for Suspension®" were determined to be bioequivalent whether under fasted or fed conditions by measurement of cis-, trans- and total cefprozil. ClinicalTrials.gov identifier, NCT04414254.

The composition and structure of polymer largely determine the properties of its final products. As a novel polymer material, the composition, structure, and properties of the isotactic polypropylene/polybutene-1 in-reactor alloy (iPP/iPB alloy) synthesized by sequential two-stage polymerization with Ziegler-Natta catalyst were correlated for the first time in this work. The iPP/iPB alloy was fractionated by temperature rising elution fractionation (TREF) in a broad temperature ranged from −30 °C to 140 °C, and the chain microstructures and sequence distributions of isolated fractions were analyzed by DSC, GPC, 13C-NMR, and FTIR. The iPP/iPB alloy was composed of five components, namely high isotactic PB (iPB, 85.8 wt%), medium isotactic PB (mPB, 5.1 wt%), poly((butene-1)-block-propylene) copolymers (PB-b-PP, 4.1 wt%) which contained PB and PP blocks with different lengths according to the isolation temperature, isotactic PP (iPP, 2.7 wt%), and atactic PB (aPB, 2.3 wt%). Compared to other commercial pipe materials, the iPP/iPB alloy presented outstanding thermal creep resistance and gas permeability resistance, high strength and low deformation at high temperature, and appropriate flexural strength. The roles of PP and PB-b-PP components in the alloy were interpreted. This work is expected to elucidate the potential application of iPP/iPB alloy as pipe materials and provide solutions for the design and synthesis of high performance pipe materials.

The catalytic activity and stereospecificity of olefin polymerization by using heterogeneous TiCl4/MgCl2 Ziegler-Natta (Z-N) catalysts are determined by the structure and nature of active centers, which are mysterious and fairly controversial. In this work, the propylene polymerization kinetics under different polymerization temperatures by using Z-N catalysts were investigated through monitoring the concentration of active centers [C*] with different tacticity. SEM was applied to characterize the catalyst morphologies and growing polypropylene (PP) particles. The lamellar thickness and crystallizability of PP obtained under different polymerization conditions were analyzed by DSC and SAXS. The PP fractions and active centers with different tacticity were obtained with solvent extraction fractionation method. The catalytic activity, active centers with different tacticity and propagation rate constant kp, fragmentation of the catalyst, crystalline structure of PP are correlated with temperature and time for propylene polymerizations. The polymerization temperature and time show complex influences on the propylene polymerization. The higher polymerization temperature (60 °C) resulted higher activity, kp and lower [C*], and the isotactic active centers Ci* as the majority ones producing the highest isotactic polypropylene (iPP) components showed much higher kp when compared with the active centers with lower stereoselectivity. Appropriate polymerization time provided full fragmentation of the catalyst and minimum diffusion limitation. This work aims to elucidate the formation and evolution of active centers with different tacticity under different polymerization temperature and time and its relations with the fragmentation of the PP/catalyst particles, and provide the solutions to the improvement of catalyst activity and isotacticity of PP.

Objective To evaluate the pharmacokinetics and bioequivalence between Sitagliptin Phosphate/metformin Hydrochloride Tablets (test formulation) at a single dose of 50mg/850mg and Sitagliptin Phosphate/metformin Hydrochloride Tablets (reference formulation, JANUMET®) at a single dose of 50mg/850mg in healthy Chinese subjects.Methods The study was designed as a randomized, open-lable, two-period double-crossover trial. A total of 24 volunteers under fasting condition and 24 subjects under fed condition were given a single oral dose of 50mg/850mg Sitagliptin Phosphate/metformin Hydrochloride Tablets of test and reference, respectively. Liquid chromatography Tandem mass spectrometry (LC-MS/MS) method was used to determine the concentrations of sitagliptin and metformin in the plasma of subjects. The pharmacokinetic parameters were calculated by WinNonlin 7.0 program and the bioequivalence was evaluated by SAS 9. 4program. Results The 90% confidential interval (CI) of geometric mean ratio under fasting condition for Cmax, AUC0-t and AUC0-∞ of sitagliptin between the test group and the reference group were 101.70%-120.62%, 99.81%-105.61%, 100.27%-106.12% and metformin were 90.39%-111.48%, 94.76%-109.12%, 95.76%-110.38%. The 90% CI of geometric mean ratio under fed condition for Cmax, AUC0-t and AUC0-∞ between the test group and the reference group were 102.12%-117.31%, 100.80%-107.81%, 100.82%-107.78% and metformin were 95.53%-105.22%, 92.76%-103.07%, 93.40%-104.14%. Both were generally well tolerated.Conclusion The two formulations of Sitagliptin Phosphate/metformin Hydrochloride Tablets were bioequivalent under fasting and fed condition in healthy Chinese subjects.Trial registration Clinical Trial Registry (trial ID: NCT04877106).

We report on a 6-year and 11-month old girl with short stature, microcephaly, proboscis nose, small teeth, left breast Tanner stage II, and nasopharynx adenoid hypertrophy. Her gestational age was ...

For the solid-solid transformation from form II to form I of isotactic polybutene-1 (iPB), the temperature dependence of form I nucleation and growth was deemed to control the transformation process. However, the relationship between form I formation and form II disappearance in the transformation process is not clear. In this work, the spontaneous crystal transformation from form II to I of iPB with 81 mol% mmmm sequence concentration is studied firstly by tracking the two processes, the decay of form II and the yielding of form I in a wide range of temperature spanning from 0 °C to 50 °C and in a long transformation time ranging from 5 min to 65 days with in situ FTIR and WAXD. Unlike the literature reports, the decay rate of form II is firstly found to be lower than the yielding rate of form I at all studied temperatures, especially at low transition temperature. This is attributed to the amorphous chains which locate near crystal lamella participating into the nucleation of form II. The regular chain folding and growth of iPB form I from amorphous chains containing short isotactic sequences also lead to an increase in crystallinity of form I compared with that of initial form II crystallized at 60 °C. An increase in the annealing temperature results in decrease in crystallinity and increase in lamellae thickness of iPB form I.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause the most serious pandemics of Coronavirus Disease 2019 (COVID-19), which threatens human health and public safety. SARS-CoV-2 spike (S) protein uses angiotensin-converting enzyme 2 (ACE2) as recognized receptor for its entry into host cell that contributes to the infection of SARS-CoV-2 to hosts. Using computational modeling approach, this study resolved the evolutionary pattern of bonding affinity of ACE2 in 247 jawed vertebrates to the spike (S) protein of SARS-CoV-2. First, high-or-low binding affinity phenotype divergence of ACE2 to the S protein of SARS-CoV-2 has appeared in two ancient species of jawed vertebrates,Scyliorhinus torazame(low-affinity, Chondrichthyes) andLatimeria chalumnae(high-affinity, Coelacanthimorpha). Second, multiple independent affinity divergence events recur in fishes, amphibians-reptiles, birds, and mammals. Third, high affinity phenotypes go up in mammals, possibly implying the rapid expansion of mammals might accelerate the evolution of coronaviruses. Fourth, we found natural mutations at eight amino acid sites of ACE2 can determine most of phenotype divergences of bonding affinity in 247 vertebrates and resolved their related structural basis. Moreover, we also identified high-affinity or low-affinity-associated concomitant mutation group.The group linked to extremely high affinity may provide novel potentials for the development of human recombinant soluble ACE2 (hrsACE2) in treating patients with COVID-19 or for constructing genetically modified SARS-CoV-2 infection models promoting vaccines studies. These findings would offer potential benefits for the treatment and prevention of SARS-CoV-2.

Blending isotactic polybutene-1 (PB) with isotactic polypropylene (PP) is a facial strategy to improve the mechanical properties and promote polymorphous transformation of PB. As the immiscible polymer pairs with strong crystallizability, the interactions between PP and PB in the melt state influence the subsequent processes like phase separation and crystallization, and then determine the crystalline structures and properties of the blends. Herein, two kinds of poly(butene-block-propylene) (PB-b-PP) copolymers with different sequence structures fractionated from PB/PP in-reactor alloy using temperature rising elution fractionation were utilized to compatibilize the PB/PP (80/20) blend. The phase morphologies, crystallization kinetics of PP and PB phases, and crystalline structures in PB/PP/PB-b-PP blends were characterized by phase contrast optical microscopy (PCOM), differential scanning calorimeter (DSC), and small-angle X-ray scattering (SAXS). The PB-b-PP copolymer with longer PP blocks (A) showed more satisfied compatibilization for PB/PP blends and PB/PP/PB-b-PP-2.5 blend with 2.5 wt% copolymer as compatibilizer exhibited the most stable phase morphology with the smallest PP domains in melt state at 200 °C. During isothermal crystallization processes of the PB/PP/PB-b-PP blends at 135 °C for PP crystallization and then 90 °C for PB crystallization, the crystallization rate including nucleation rate and nucleation density, and crystallinity of PP and PB (form II) increased, and achieved the largest when the copolymer concentration was 2.5 wt% in PB/PP/PB-b-PP blend. The copolymer A significantly accelerated crystallization rate of PP compared with that of copolymer B. The PB/PP/A-2.5 blend with the largest lamellae thickness and highest crystallinity of PB form I, combined with the smallest spherulites, exhibited the highest modulus, tensile strength and toughness. The compatibilizing mechanism and roles of PB-b-PP copolymers for PB/PP blends were discussed to understand the physical and mechanical behaviors of the blends.

The grey wolf (Canis lupus) is one of the most widely distributed terrestrial mammals, and its distribution and ecology in Europe and North America are largely well described. However, the distribution of grey wolves in southern China is still highly controversial. Several well-known western literatures stated that there were no grey wolves in southern China, while the presence of grey wolves across China has been indicated in A Guide to the Mammals of China, published by Princeton University Press. It is essential to solve this discrepancy since dogs may have originated from grey wolves in southern China. Therefore, we systematically investigated Chinese literatures about wild animal surveys and identified more than 100 articles and books that included information of the distribution of grey wolves in China. We also surveyed the collections of three Chinese natural museums and found 26 grey wolf skins specimens collected across China. Moreover, we investigated the fossil records in China and identified 25 archaeological sites with wolf remains including south China. In conclusion, with the comprehensive summary of Chinese literatures, museum specimens and fossil records, we demonstrate that grey wolves do distribute across all parts of the Chinese mainland, including the most southern parts.

Solvent annealing is a facile method for changing the aggregated microstructure and physical properties of polymer materials. In this paper, we addressed the effects of solvent vapor annealing, including chloroform and water vapor, on the polymorphic transformation in both hot-pressed film and electrospun nonwoven of isotactic polybutene-1 (PB-1) by means of in situ Fourier transform infrared spectroscopy (FTIR). The pretty rapid transition rate caused by the increased motion of molecular chains under chloroform vapor is associated with a lowest crystallinity. Also, a decreased crystallinity with the crystal transition occurred in electrospun nonwovens resulting from the relaxation of the stretched molecular chains into amorphous state rather than realignment into crystal form I predominating the crystal transition process.

A series of isotactic polybutene-1/polypropylene (PB/PP) in-reactor alloys were prepared by Ziegler-Natta catalyst using sequential two-stage polymerization technology. Temperature rising elution fractionation (TREF) combining with DSC, GPC and 13C-NMR were used to analyze the compositional heterogeneity of the resulting PB/PP alloys. Fractions in the PB/PP alloys, including isotactic polybutene-1, isotactic polypropylene, atactic polybutene-1, a series of copolymers with different length of PB segments, PP segments, and poly(propylene-co-(butene-1)) segments, were isolated for the first time by TREF whereby the chain structure and sequence distribution of these fractions were characterized. A possible mechanism was proposed to explain the fraction formation in this sequential two-stage polymerization technology. The mechanical properties and polymorphic transition of the PB/PP alloys were also studied and correlated with the fraction structure and distribution.

Pedestrian evacuation is actually a process of behavioral evolution. Interaction behaviors between pedestrians affect not only the evolution of their cooperation strategy, but also their evacuation paths-scheduling and dynamics features. The existence of interaction behaviors and cooperation evolution is therefore critical for pedestrian evacuation. To address this issue, an extended cellular automaton (CA) evacuation model considering the effects of interaction behaviors and cooperation evolution is proposed here. The influence mechanism of the environment factor and interaction behaviors between neighbors on the decision- making of one pedestrian to path scheduling is focused. Average payoffs interacting with neighbors are used to represent the competitive ability of one pedestrian, aiming to solve the conflicts when more than one pedestrian competes for the same position based on a new method. Influences of interaction behaviors, the panic degree and the conflict cost on the evacuation dynamics and cooperation evolution of pedestrians are discussed. Simulation results of the room evacuation show that the interaction behaviors between pedestrians to a certain extent are beneficial to the evacuation efficiency and the formation of cooperation behaviors as well. The increase of conflict cost prolongs the evacuation time. Panic emotions of pedestrians are bad for cooperation behaviors of the crowd and have complex effects on evacuation time. A new self-organization effect is also presented.

Dingoes(Canis dingo)are wild canids living in Australia. They have lived isolated from both the wild and the domestic ancestor and are a unique model for studying feralization, the process in which a domestic species escapes human control, adapts to the wild, and diverges from the domestic ancestor into a genetically distinct population. Here, we sequenced the genomes of 10 dingoes and 2 New Guinea Singing Dogs, to study the origins and feralization process of the dingo. Phylogenetic and demographic analyses show that dingoes originate from domestic dogs in southern East Asia, which migrated via Island Southeast Asia to reach Australia 4300-5000 years ago, and subsequently diverged into a genetically distinct population. Selection analysis identified 99 positively selected genes enriched in starch and fat metabolism pathways, indicating a diet change during feralization of dingoes. Interestingly, we found that 14 genes have shifted allele frequencies compared to dogs but not compared to wolves. This suggests that the selection affecting these genes during domestication of the wolf was reversed in the feralization process. One of these genes,ARHGEF7,may promote the formation of neural spine and synapses in hippocampal neurons. Functional assays showed that an A to G mutation inARHGEF7,located in a transcription factor-binding site, decreases the endogenous expression. This suggests thatARHGEF7may have been under selection for behavioral adaptations related to the transitions in environment both from wild to domestic and from domestic back to wild. Our results indicate that adaptation to domestication and feralization primarily affected different genomic regions, but that some genes, related to neurodevelopment, metabolism and reproduction, may have been reversibly affected in the two processes.

The dog mtDNA diversity picture from wide geographical sampling but from a small number of individuals per region or breed, displayed little geographical correlation and high degree of haplotype sharing between very distant breeds. For a clear picture, we extensively surveyed Iranian native dogs (n = 305) in comparison with published European (n = 443) and Southwest Asian (n = 195) dogs. Twelve haplotypes related to haplogroups A, B and C were shared by Iranian, European, Southwest Asian and East Asian dogs. In Iran, haplotype and nucleotide diversities were highest in east, southeast and northwest populations while western population had the least. Sarabi and Saluki dog populations can be assigned into haplogroups A, B, C and D; Qahderijani and Kurdi to haplogroups A, B and C, Torkaman to haplogroups A, B and D while Sangsari and Fendo into haplogroups A and B, respectively. Evaluation of population differentiation using pairwise FST generally revealed no clear population structure in most Iranian dog populations. The genetic signal of a recent demographic expansion was detected in East and Southeast populations. Further, in accordance with previous studies on dog-wolf hybridization for haplogroup d2 origin, the highest number of d2 haplotypes in Iranian dog as compared to other areas of Mediterranean basin suggests Iran as the probable center of its origin. Historical evidence showed that Silk Road linked Iran to countries in South East Asia and other parts of the world, which might have probably influenced effective gene flow within Iran and these regions. The medium nucleotide diversity observed in Iranian dog calls for utilization of appropriate management techniques in increasing effective population size.

Natural selection in domestic dogs is of great interest in evolutionary biology since dogs have migrated to every inhabited continent of the world alongside humans, and adapted to diverse environments. Here, we explored their demographic history and genetic basis of adaptation to the tropical African environment using whole genome analyses of 19 African indigenous dogs from Nigeria. Demographic analysis suggests that the ancestors of these dogs migrated into Africa from Eurasia 14,000 years ago and underwent a severe founder effect before population expansion. Admixture analysis further reveals that African dog genomes contain about 1.88–3.50% introgression from African golden wolves (Canis anthus). Population genetic analysis identifies 50 positively selected genes linked with immunity, angiogenesis, ultraviolet protection, as well as insulin secretion and sensitivity that may contribute to adaptation to tropical conditions. One of the positively selected genes, adhesion G protein-coupled receptor E1 (ADGRE1), has also been found to be association with severe malaria resistance in African human populations. Functional assessments showed that ADGRE1 provides protective host defense against Plasmodium infections. This result, together with the fact that the inflammatory response to canine babesiosis is similar to complicated falciparum malaria in humans, support the dogs as a model for the study of malaria control and treatment. This is a pre-copyedited, author-produced version of an article accepted for publication in [Molecular biology and evolution] following peer review. Locked until 10.10.2018 due to copyright restrictions. The version of record is available online at: https://academic.oup.com/mbe/article/35/2/287/4316110

Background East Asian dog breeds are one of the most ancient groups of dogs that radiated after the domestication of the dog and represent the most basal lineages of dog evolution. Among these, the Chow Chow is an ancient breed that embodies very distinct morphological and physiological features, such as sturdy build, dense coat, and blue/purple tongue. Results Using a Restricted site Associated DNA (RAD) sequencing approach, we sequenced the genomes of nine Chow Chows from China. Combined with a dataset of 37 canid whole genome sequencing (WGS) from several published works, we found that the Chow Chow is one of the most basal lineages, which originated together with other East Asian breeds, such as the Shar-Pei and Akita. Demographic analysis found that Chow Chows originated from the Chinese indigenous dog about 8300 years ago. The bottleneck leading to Chow Chows was not strong and genetic migration between Chow Chows and other populations is low. Two classes of genes show strong evidence of positive selection along the Chow Chow lineage, namely genes related to metabolism and digestion as well as muscle/heart development and differentiation. Conclusions Dog breeds from East Asia, including the Chow Chow, originated from Chinese indigenous dogs very early in time. The genetic bottleneck leading to Chow Chows and migrations with other populations are found to be quite mild. Our current study represents an early endeavor to characterize the origin of East Asian dog breeds and establishes an important reference point for understanding the origin of ancient breeds in Asia. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3525-9) contains supplementary material, which is available to authorized users.

Deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly, NH2, Del II), an endogenous linear heptapeptide, is a highly selective agonist of the δ-opioid receptor. To study the effect of the position 4 residue (Glu) on the opioid activity of Del II, we designed and synthesized three analogues of Del II by solid-phase peptide synthesis. They were [Val4, Glu5]Del II, [Val4, Glu6]Del II and [Gly4, Glu7]Del II. To study the effect of spin labeling on peptide bioactivities, all the peptides were labeled using a free radical. The labeling material was a stable nitrogen-oxygen free radical which was linked to the N-terminal via an amide bond. We investigated the opioid bioactivities of these analogues both in vivo and in vitro, and concluded that the differences in opioid activity of Del II and its analogues were due to structural differences. When the Glu residue is at position 5 or 6, the internal hydrogen bonds in Del II are affected and there is a change in three-dimensional structure and opioid activity. The antinociceptive activity of all the peptides decreased after spin labeling. This indicates that the stable nitrogen-oxygen free radical is a dual-function spin-labeling molecule.

The second zinc finger fragment of Sp1 (Sp1-ZF2), its mutant (Sp1-ZF2/HT. E(20) --H, R(23) --T), and two mimic analogues (ZF20 and ZF15) were synthesized by stepwise solid phase technique. The CD spectra and UV-visible spectrum with CoC1(2) indicated that the formation of zinc finger structure was affected not only by the hydrophobic amino acids but also by the change of the distance between Cys and His. Gel-retardat ion electrophoresis assays indicated that the Glu and Arg residues are very important for recognition. A single zinc finger like Sp1-ZF2 is able to bind DNA sequence specifically.

A specific, sensitive capillary multi-dimensional gas chromatographic method with thermionic specific detection (TSD) combined with internal standard methodology to identify ethyl carbamate (EC), a well known carcinogen, in various fermented alcoholic beverages is described. The basic procedures for sample preparation were similar to a modification of the LCBO (Liquor Control Board of Ontario) procedure, except that isopropyl carbamate (i-PC) was used as an internal standard. In the multi-dimensional gas chromatographic process, EC and i-PC were co-eluted on a polar capillary precolumn of BP-20, and then switched together to a non-polar OV-1 analytical column by the heart-cutting technique to resolve them and finally detected by TSD. The linear range of the calibration graph was from 10 to 550 ppb with a correlation coefficient of 0.9996. For a liquor containing 124.6 ppb of EC, the relative standard deviation was 2.0% and the detection limit was 1 ppb.

To assess the combating performance of complex operational system dynamically, and to fix quantify various performance parameters of system, a evolving topological model based on the interacting and non-linear priority growth of new nodes and internal edges which substitutes real military system and the dynamic development has been abstracted, with reference to social network an complex network theory, such as Transit-Stub model based on hierarchical structure, BA model based on the degree of node, GLP and PFP models and multi-local world model. And this model was established and simulated by MATLAB software according to various rules defined in model. Many topological properties are discussed after evolving with different conditions and time. Finally, evolvement process of system's characters is acquainted and applied to the practice of military construction. By analytical-numerical method and experimental simulation, it draws the conclusion that operational system is a scale free network while the feature of small world is unobvious. This may because the military is a well-organized system, and has a stronger self-adapting power compared with Internet.

Deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2, Del II) is a highly selective agonist of δII opioid receptor [1], which was isolated from the frog Phyllmedusa Sauvagei in 1989 [2]. DeltorphinII and dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-SerNH2, DRM), which is the μ-receptor selective agonist [3], share common generalized N-terminal tripeptide sequences, H-Tyr1-D-Ala2-Phe3, which comprise the message domains of these peptides. The critical structural differences between these two peptides lie in the C-terminal tetrapeptide region, the address domain, adjacent to the N-terminal message domain. Deltorphin II analogs were selected to test the hypothesis of Schwyzer [4] that flexible .peptide hormones contain “synchnologic organization”, i.e., the polypeptide sequence is composed of proximal regions which exist as distinct message and address domains. The message domain provides information for signal transduction leading to a biological response, while the address domain’ primarily influences binding affinities and accommodates the elements of selectivity without necessarily affecting transduction. In order to expand our understanding of the characteristics of the Cterminal tetrapeptide address domain of deltorphin II on opioid receptor affinities and selectivities, studies were conducted with several analogs of the peptide in which the spatial distribution of the negatively charged residues was repositioned relative to the hydrophobic residues. Its position 4 is a negative charged amino acid Glu. To study the effect of Glu on the function of deltorphin II, we designed and synthesized a series of analogs of deltorphin II by SPPS (solid phase peptide synthesis), they were: (fig. 1).