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Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1’s interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19and 20were designed for an AS assay. Structure-based optimization led to compounds 30and 31with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds’ affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

Airborne pests pose a major challenge in agriculture. Integrated pest management programs have been considered a viable response to this challenge, and pest forecasting can aid in strategic management decisions. Annually recurrent areawide sugarcane aphid [Melanaphis sacchari(Zehntner) (Hemiptera: Aphididae)] infestations of sorghum [Sorghum bicolor(L.) Moench (Poales: Poaceae)] in the Great Plains of North America is one of such challenges. As part of the response, a spatially-explicit individual-based model was developed that simulates sugarcane aphid infestations over the southern-to-central part of the region. In this work, we evaluated model forecasts using 2015–2018 field data. The ranges of forecasted days of first infestation significantly overlapped with those observed in the field. The average days of first infestation observed in the field were approximated by the model with differences of less than 28 days in Texas and southern Oklahoma (2015–2018), and in northern Oklahoma (2016–2017). In half of these cases the difference was less than 14 days. In general, the modeled average day of first infestation was earlier than the observed one. As conceptual modeling decisions may impact model forecasts and as various socio-environmental factors may impact spatio-temporal patterns of field data collection, agreement between the forecasts and the observed estimates may vary between locations and seasons. Predictive modeling has the potential to occupy a central position within areawide integrated pest management programs. More detailed consideration of local agricultural practices and local environmental conditions could improve forecasting accuracy, as could broader participation of producers in field monitoring efforts.

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3led to the identification of compound 9(OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7fas a highly potent AMCase inhibitor (IC50values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7fin the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.

Lenvatinib plus pembrolizumab demonstrated antitumor activity and acceptable safety in previously treated metastatic NSCLC. We evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in metastatic NSCLC in the LEAP-007 study (NCT03829332/NCT04676412).

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure–activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30was significantly reduced when compared to the earlier reported chitinase inhibitors.

The efficiency of ultrasound hyperthermia for anti-cancer treatments such as radiotherapy or chemotherapy can be improved by using sonosensitizers, which are materials that enhance the attenuation and dissipation of acoustic energy. We propose the use of magnetic nanoparticles as sonosensitizers because of their biocompatibility, nontoxicity, and common use in several medical applications. A magnetic material was synthetized and then incorporated in the form of a magnetic fluid in agar tissue-mimicking phantoms. Ultrasound hyperthermia studies were conducted at various ultrasound frequencies and concentrations of magnetic nanoparticles in the phantoms. The theoretical modeling based on a heat transfer equation and the experimental results show good agreement and confirm that the temperature rise during ultrasound heating in tissue-mimicking phantoms doped with sonosensitizers is greater than that in a pure agar phantom. Furthermore, on the basis of Pennes’ bio-heat equation, which takes into consideration the blood perfusion and metabolic heat, the thermal dose and lesion shapes after sonication were determined for a hypothetical tissue.

Ferritins are proteins, which serve as a storage and transportation capsule for iron inside living organisms. Continuously charging the proteins with iron and releasing it from the ferritin is necessary to assure proper management of these important ions within the organism. On the other hand, synthetic ferritins have great potential for biomedical and technological applications. In this work, the behavior of ferritin during the processes of iron loading and release was examined using multiplicity of the experimental technique. The quality of the protein’s shell was monitored using circular dichroism, whereas the average size and its distribution were estimated from dynamic light scattering and transmission electron microscopy images, respectively. Because of the magnetic behavior of the iron mineral, a number of magnetooptical methods were used to gain information on the iron core of the ferritin. Faraday rotation and magnetic linear birefringence studies provide evidence that the iron loading and the iron-release processes are not symmetrical. The spatial organization of the mineral within the protein’s core changes depending on whether the iron was incorporated into or removed from the ferritin’s shell. Magnetic optical rotatory dispersion spectra exclude the contribution of the Fe(II)-composed mineral, whereas joined magnetooptical and nuclear magnetic resonance results indicate that no mineral with high magnetization appear at any stage of the loading/release process. These findings suggest that the iron core of loaded/released ferritin consists of single-phase, that is, ferrihydrite. The presented results demonstrate the usefulness of emerging magnetooptical methods in biomedical research and applications.

Loblolly pine (Pinus taeda L.) is an intensely studied species that has become a model system for conifers. It is one of the most important commercial crops in the southeastern United States and grows across a vast territory. Due to exposure to this current diverse environment and the fluctuating climatic conditions of the past, it has likely accumulated substantial variation in adaptive trait and wood strength related genes. We merged a set of newly collected and previously published genomic DNA sequence data and analyzed them for departures from neutrality in 32 drought tolerance and wood strength related candidate genes using neutrality tests, such as Tajima’s D, HKA, MK and nonsynonymous to synonymous substitutions ratio (Z-test). Three other major Southern pines closely related to P. taeda (Pinus echinata Mill., P. elliottii Engelm., and P. palustris Mill.) were used as outgroups in interspecific tests. In three loci (4-coumarate: CoA ligase, putative cell-wall protein and trans-cinnamate 4-hydroxylase 2) neutrality was rejected by both intra- and interspecific tests, consistent with purifying selection. Neutrality was also rejected in several other loci (alpha-tubulin, arabinogalactan 4, arabinogalactan 6, cinnamate 4-hydroxylase 1, cinnamoyl CoA reductase, cinnamyl alcohol dehydrogenase, caffeoyl CoA O-methyltransferase 1, early response to drought 3, glycine hydroxymethyltransferase, ABI1 protein phosphatase 2C-like, putative wall-associated protein kinase, and unknown gene ug_2-498); however, these results are difficult to interpret because only one of the tests proved significant. This study contributes to the ongoing discussion about natural selection in putative adaptive genes in loblolly pine. However, unambiguous interpretation of the results often remains problematic.

Influence of hydraulic oil viscosity on the volumetric losses in a variable capacity piston pumpThe variable capacity piston pumps are elements of the great power and highest energy efficiency hydrostatic drives. They are used in the drive systems of ship equipment such as deck cranes, steering gears, main propulsion of smaller vessels. The laboratory and simulation investigations of the influence of liquid viscosity on the variable capacity displacement pump energy losses have not been so far performed.The paper presents results of the investigations of impact the hydraulic oil viscosity has on the volumetric losses in a piston pump operating in the full range of its capacity and oil pressure.

The relation between chemical composition, crystal structure and electrical features of lead germanate, (Pb5–xBax)Ge3O11, pure and doped with Ba (x = 0, 0.10, 0.25) was studied. The O deficiency and GeO2 precipitation was found in the crystals studied. In the case of the Ba-doped crystals, the XPS lines width (FWHM) variation suggests structural local disorder. The valence band is placed near 3 eV and it shows an exponential tail, which is ascribed to existence of energy levels correlated to defects. Both the valence band edge shift and the degree of disorder deduced from the change in the XPS lines width vary non-linearly with the concentration of the Ba ions. The ac conductivity activation energy values Ea = 0.55–0.85 eV indicate electric conductivity of lead germanate is determined by local energy levels originated from point defects. The analysis of the imaginary part of the electric modulus M ″(T, f) exhibited the electronic relaxation process related to electric conductivity, for which the activation energy EM = 0.63–0.72 eV, and the characteristic times τ0 of the order of 10–13 s were evaluated. The crystal structure parameters and several of the electrical conduction parameters exhibit non-monotonic dependence on the Ba concentration. It was deduced that Ba ions contributed to the mentioned phenomena by two opposite mechanisms. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted.

To study the influence of a 3-week hiking vacation at moderate (1700 m) and low altitude (LA) (200 m) on key-markers of the metabolic syndrome, 71 male volunteers (age 36–66 yr old) with the metabolic syndrome [according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP-ATP III) — or World Health Organization (WHO) — definition] participated in the study and were randomly assigned into a moderate altitude (MA) group (1700 m, no. 36) and a low altitude (LA) group (200 m, no. 35). The 3-week vacation program included 12 moderate-intensity guided hiking tours [4 times/week, 55–65% heart rate maximum (HRmax)] with a total exercise time of 29 h plus moderate recreational activities. Both study groups had a comparable and balanced nutrition with no specific dietary restrictions. Anthropometric, metabolic and cardiovascular parameters were measured 10–14 days before vacation, several times during the 3-week vacation, 7–10 days and 6–8 weeks after return. All participants tolerated the vacation without any adverse effects. Body weight, body fat, waist-circumference, fasting glucose, total cholesterol, LDL-cholesterol (LDL-C), plasma fibrinogen, resting systolic and diastolic blood pressure were significantly decreased over time in both study groups. In the LA group, fasting insulin and homeostasis model assessment (HOMA)-index were significantly decreased one week after return. Relative cycle ergometry performance was significantly increased after return compared to baseline. In both study groups, waist-to-hip ratio (WHR), 2-h oral glucose tolerance test (OGTT), HDL-cholesterol (HDL-C), and triglycerides remained unchanged. The 3-week vacation intervention at moderate and LA had a positive influence on all key-markers of the metabolic syndrome. No clinically relevant differences could be detected between the study groups. A hiking vacation at moderate and LA can be recommended for people with stable, controlled metabolic and cardiovascular risk factors.

Solid thin films of lubricants are often used as protection coatings of working surfaces in frictional contacts. Usually, these films have to contain stable and tribologically active additives like, for example, molybdenum disulphide or graphite. In this work chemically modified silica was investigated as a potential matrix of nanocomposite lubrication films. The sol-gel technique was used with tetraethoxysilane (TEOS) and triethoxymethylsilane (TEMS) as precursors of organo-silica thin films. Dip coating was applied as the method of film formation. Introducing a methyl group into silica by adding TEMS during sol-gel synthesis of silica films strongly increases their adhesion to the coated materials, which gives possibilities for using them on steel surfaces. The chemical properties of films synthesised by the sol-gel technique were examined by FTIR spectroscopy with the use of the transmission method. The surface topography was imaged and frictional features of organo-silica films were examined by Atomic Force Microscopy (AFM).

It was the aim of this study to investigate the time course of changes in the serum concentrations of vascular endothelial growth factor (VEGF) during a regular survival training programme combined with food and fluid deprivation and during a high altitude marathon run. We studied soldiers of the Austrian Special Forces performing survival training at sea-level and marathon runners of the Posta Atletica who crossed the border between Chile and Argentina at altitudes up to 4722?m. Baseline data collected before the 1-week of survival training showed that the soldiers had normal VEGF [ n=8, 246.7?(SD 118.5)?pg?·?ml -1] serum concentrations which remained unchanged during the course of the study. Before the high altitude marathon the subjects showed normal VEGF serum concentrations [178?(SD 84.5)?pg?·?ml -1]. After the run VEGF concentrations were found to be significantly decreased [41.0?(SD 41.6)?pg?·?ml -1, P?

The paper presents a hypothesis concerning a differential formula for the production function. The problem of specifying the production function is attempted to be solved using a systems approach. The differential formula of the production function represents the structure of connection between flow and potential. They are the signal variables of the production process. These variables are represented in the differential production function by the new economic categories: "on production force" and "production front". The production function as a differential equation of the production process is constituted by the new signal variables. The problem of finding relationships between the differential formula and traditional formulae of the production function is slated.

AbstractThe thermal expansion coefficients, αi, of deuterated (90%) TGS crystals has been measured for the three main directions a, b, c* in the temperature range 300-400 °K. The anomalous part of the thermal expansion has been examined by fitting the data to logarithmic corrections with powers 1 and 1/3. The electrostriction coefficients Qi22for DTGS have been calculated from dilatation measurements. The results obtained have been compared with those for TGS crystals.

AbstractUniaxial pressure influence on the phase transition of deuterated (0-90%) TGS crystals are reported for the three directions- a, b, c*. The coefficients γi(γi≏ ∂Tc/∂xi) are established to be lineary dependent on the uniaxial pressure. The coefficient ξ of the fourth power of P in the free energy expansion is practically uniaxial pressure independent. The main changes of γiobserved in the ac* plane are related to “long” O-H-O and N-H-O bonds. The values of the γicoefficients are in well agreement with those calculated from the Ehrenfest relation.

The behaviour of hysteresys loops of TGS single crystals under variable uniaxial stress X (0-800 dyn/cm2) along the a, b and c. (|a,b) axes has been investigated at fixed tempreatures near the zero stress transition temperature, Tc(0), resulting in stress-induced ferro-paraelectric transitions. The cubic coefficient, ξ, appearing in the equation of state, E=χP+ξP3decreases for X ‖ a, and x‖b, and increases for X ‖ c. with increasing stress, thus approaching the tricritical point in the latter case.

An experimental device to test energy conversion of thermal to electric energy by means of ferroelectric materials has been used to investigate thin plates of PZT ceramics (near the Flt -Fht transition temperature) and TGS-alanine single crystals (near the Curie temperature). Preliminary results for PZT plates give efficiencies of the order of 2.5 10--3 the Carnot efficiency and specific power outputs equivalent to 165 watts/m3.

Dispersion of optical rotatory power ρ of TGS and DTGS crystals in the spectral range of 444 nm-632.8 nm at 293 K has been measured. The change in sign of the optical rotatory power during switching of domains was observed. Linear relation between optical rotatory power and spontaneous polarization as well as relation ∼ (Tc - T)1/2 were confirmed for both crystals. The interpretation of the results obtained showed that the optical activity is due to the spiral arrangement of glycine molecules and non-planar structure of glycine I in ferroelectric phase.

Ferroelectric perovskites, in particular KNbO3, PbTiO3 and BaTiO3, are characterized by discontinuities in the dielectric constant at the tetragonal-cubic transition (T*) as well as by the abrupt disappearance of the spontaneous polarization which goes from a minimum finite value Ps* =Ps (T) to zero at T=T*. It is shown that, taking into account quadrupolar and higher order terms into the effective field acting on the elementary dipoles lattice, good fits to the observed Ps(T) in a wide temperature range below T* and to the inverse dielectric constant discontinuity (C/Tc)[ε+-1(T*)-ε--1(T*)] at T⋍T* are obtained for these three perovskites.

It is shown that a selfconsistent calculation of the maximum amount of thermal hystersis accompanying discountinous ferroelectric transtion can be made if one takes into account the quadrupolar contribution to the effective ferroelectric field. Comparison of calculated and observed thermal hystersis in sereral ferroelectrics belonging to different families shows fair agreement.

Ultrasonics (10 MHz and 50 MHz) and Brillouin (18.2 Hz and 19.2 Ghz) measurements of the longitudinal sound velocity in TGS propagating along the crystallographic c-axis (⊥ to the ferroelectric b-axis) have been performed in the vicinity of the transition temperature Tc=49.3°C. The data confirm a Debye type relaxation behavior with a polarization relaxation time of the form τ=A(Tc-T)-1 for T < Tc which is in fair quantitative agreement with the relaxation time from dielectric measurements at high frequencies.

Abstract: Electrical carotid sinus nerve stimulation (CSNS) via an implanted electrode receiver assembly, radio frequency coupled to an external signal generator, is an experimental therapy for hypertension and angina pectoris. CSNS increases afferent information to the central nervous system exerting neurally regulated decreases in heart rate, stroke volume, and blood pressure. No nonspecific side effects are observed, in contrast to drug therapy. A nerve pacemaker system is described and compared to the commonly used open-loop stimulator system (fixed frequency and intensity CSNS). It is a closed-loop system, controlled by heart rate (as an indicator of the state of “arousal” and of sympathetic activity) and, thereby, feedback-controlled by its therapeutic effects. The miniaturized (hybrid technology) system consists of an ECG amplifier, a stimulus pattern memory with I-O periphery and a transmitter, including an antenna coil to be coupled to the implanted assembly. Stimulus parameters (frequency and amplitude of impulses) are optimized for each patient individually. Stimulus patterns (pulse synchronous amplitude modulated groups of impulses) are adapted to the patient's cardiovascular situation. The nerve pacemaker may be an alternative to drug therapy or major surgery in both diseases. Compatible with the open-loop system, it replaces the first step in previously treated CSNS patients.

Dispersion and temperature dependence of optical rotatory power along the optical axis of NaNH4C4H4O6 x 4H2O crystals has been measured. Gyration tensor components g33 are measured, g22 and g11 are tentatively calculated.

Dispersion of optical rotatory power σ temperature dependence of σ and electrogyration hysteresis loop of TGSe crystals have been measured. The origin of OA in TGS type crystals is discussed.

The temperature dependence of optical birefringence for TGS, DTGS, TGSe and DTGSe with different degrees of deuterium has been measured between 12K - 370K. Three characteristic temperatures for all crystals and a discontinuity in Δn at Tc for DTGSe are observed.

The low-temperature dependence of pyroelectric charge, piezoelectricity, optical birefringence, dielectric constants and elastic properties of Cs2CuCl4 crystals have been studied. The results obtained suggest phase transitions at ∼ 140 K and ∼218 K.

Dispersion and temperature dependence of the optical angle 2V, and optical activity as well as absorption UV spectra of LiNH4C4H4O6xH2O single crystal are reported. The domain structure of LAT below 98K and light deflections from ferroelastic domain walls were observed and examined. It was found that there are two kinds of domains observable below Tc i.e. with the (001) domain walls and (100) domain walls, called "a" and "c" domains, respectively. Experimental results proved that its phase transition is of the second order. A comparison of the reported results with those for Rochelle salt is given.

A simple model for optical activity in ferroelectrics is presented in which the effect of the spontaneous field, associated with Ps is taken into account.

Isothermic and isobaric studies of the influence of uniaxial pressure on the phase transition of deuterated TGS are reported for three directions-X, Y, Z. The pressure coefficients γ (γi ≡ бTc/бXi) are established. It has been found that the coefficient ξ of the fourth power in the free energy expansion is practically not uniaxial pressure and temperature-dependent in the range of uniaxial pressures investigated (up to 1kbar). Similarities between purely stress and temperature-induced phase transitions are shown, and the results are analyzed using scaled variables. Phenomenological theory and the molecular origin of the ferroelectric mechanism for TGS crystals are also discussed.

In baropacing (e.g. therapeutical electrical carotid sinus nerve stimulation in open loop, as well as in closed loop by means of a baroreceptor analog) an adaptation of stimulation parameters to the individual patients sensitivity is useful, regarding optimal stimulation patterns. An alternative method to closed loop frequency modulated stimulation has been developed: Amplitude modulated stimulation was compared to other methods in animal experiments and was found to be equally effective to frequency modulation with regard to depressor response. With regard to applied stimulation energy, amplitude modulation was found to be energetically more economic. A test unit, comprising currently available stimulation methods has been developed in order to adapt method and stimulation parameters to the needs of a patient to be equipped with a stimulator. An alternative use of the analog is proposed in the control of the artificial heart.

Applying the model of the anharmonic oscillator, phenomenological expressions were derived, allowing calculation of the components of tensors describing non-linear magneto-electric susceptibilities. Detailed calculations were carried out for the pseudo-tensor of fourth order ?eeem in terms of which magneto-optical birefringence and rotation are expressed for the monocrystals KDP, DKDP, ADP, KDA, LiNbO3, LiTaO3 and NaClO3. From the results obtained it follows that non-linear magneto-electric susceptibilities, which are described by the pseudo-tensor ?eeem are of the order of 10-16 m V-1T-1.

Dispersion of optical rotatory power δ, temperature dependence of δ and electrogyration of hysteresis loops of pure and X-irradiated TGS crystals have been measured, The relation between OA and Ps and the origin of OA in TGS crystal is discussed.

Electrogyration Miller's delta Δg is checked for more than 50 crystals. The corelation between Δg and other quantites is discussed, similar relation for quadratic electrogyration is introduced.

A ‘rescuable’ plasmid containing globin gene sequences allowing recombination with homologous chromosomal sequences has enabled us to produce, score and clone mammalian cells with the plasmid integrated into the human β-globin locus. The planned modification was achieved in about one per thousand transformed cells whether or not the target gene was expressed.

Temperature dependence as well as dispersion (spectral range 457.9 to 632.8 nm) of OA for LATGS crystals with the Ala concentration, cac, equal 0.155, 0.295, and 0.370 weight % have been measured by classical method along the optical axis. The relation between OA and Ps as well as the origin of OA in TGS-like crystals is discussed.

A detailed optical activity studies of single crystals of TGS and DTGS with various deuterations in spectral range from 457,9 nm to 632,8 nm at a temperature of 293 K using a sensitive modulation technique have been carried out. Temperature dependences of the optical rotatory power ρ have been measured and linear relation between ρ and spontaneous polarization Ps has been found for both crystals. Similar relation has been given by Hermelbracht and Unruh [1] and Vlokh et al. [2] for TGS crystal. The reversibility of the rotatory power has been found by inspection of Airy spirals when ferroelectric domains are switched. Symetric and unipolar electrogiration hysteresis loops, connected with ferroelectric hysteresis loops have been observed in TGS and DTGS crystals during repolarization of domains.

An optical method which allows quantitative determination of L-alanine contents in L-alanine doped TGS crystals is described. L-alanine content was determined in (001) and (110) growth pyramids of LATGS crystals grown above and below Tc. Relation between Eband alanine content in crystals established from Devonshire's theory is in reasonable agreement with the experimerttal results.