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In this pre-specified sub-study of the POISE-3 trial, we examined the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of postoperative acute kidney injury (AKI). Altogether, 7307 patients were included from 110 hospitals in 22 countries. Patients were 45 years and older, had or were at risk of atherosclerotic disease, took at least one antihypertensive medication, and were scheduled for noncardiac surgery. Hypotension-avoidance strategy: (i) target intraoperative mean arterial pressure (MAP) 80 mm Hg or over, (ii) on day of surgery and for two days after, hold renin-angiotensin-aldosterone system inhibitors and use other antihypertensives in stepwise fashion if systolic blood pressure (SBP) 130 mm Hg or more. Hypertension-avoidance strategy: (i) target intraoperative MAP 60 mm Hg or more, (ii) continue all antihypertensives before and after surgery. Primary outcome: postoperative AKI, an increase in serum creatinine concentration of either 26.5 μmol/L or more (0.3 mg/dL or more) within 48 hours of randomization or 50% or more within seven days of randomization. The hypotension-avoidance group (3654 patients) used fewer antihypertensive medications than the hypertension-avoidance group (3653 patients); specifically, 6% vs. 38% used an ACEI or ARB on the day of surgery, and 6% vs. 47% and 7% vs. 50% one and two days after surgery, respectively. Patients also spent about half as much intraoperative time with a MAP under 80 mm Hg (27 vs. 60 minutes, respectively), but had little difference in average BP before or after surgery. There was no significant difference in AKI risk (15.1% vs. 14.4%). Results were consistent with other definitions of AKI and in patients with preexisting chronic kidney disease. Thus, a hypotension-avoidance strategy targeting a MAP greater than 80 mm Hg in the operating room and discontinued blood pressure medication during the perioperative period did not confer a lower risk of AKI compared to a hypertension avoidance strategy.

The electrification of off-grid /island villages is a critical step towards improving the techno-economic circumstances of rural regions and the overall general growth of the country. However, consistent supply from a single source is not possible in these areas. Thus, a hybrid renewable energy system performs better in these conditions. The research challenge now is to identify the optimal combinations of HRES from the available resources in a specific village site that can supply the power demand sustainably and to determine whether this is a cost-effective option. The present work is an endeavour to develop a sustainable and dynamic energy demand-supply model using HOMER Pro energy software in a specified off-grid rural site in Vietnam. The research presents four unique configurations of a combined energy system for Vietnam's island settlements, incorporating biomass-based biogas facilities, photovoltaic panels, lithium-ion batteries, and converters. Homer Pro was used for optimization and design, focusing on key performance measures such as cost of energy, net present cost, initial cost, operating cost, renewable fraction, and carbon emissions. The best HES system layout includes a 100-kW biomass-based generator, 2.62 kW photovoltaic installation, 10 lithium-ion batteries, and a 6.31 kW converter, producing 100 % renewable energy. The system's low cost of energy ($0.48), and net present cost ($25,730.89) make it an economically viable alternative, while its low CO2emissions demonstrate its commitment to reducing greenhouse gas emissions.

•T-bet acts as a tumor suppressor by enhancing interferon signaling and suppressing proliferation of malignant B cells.•T-bet expression in CLL cells is positively correlated with longer overall survival in patients with CLL.

The present article considers a modified optimal control model (MOCM) of the pilot. The main idea behind the proposed modification is moving the time delay element, initially located at the input of the model, to its output. Such relocation eliminates the need for introducing a “predictor” block to the model’s structure, which simplifies the algorithm for calculating the parameters of the optimal model. Besides a description of the modified algorithm, the paper assesses the agreement between the performance achieved using the algorithm and the results of experimental investigations. In addition, the results of modeling are compared to the results obtained using a structural model. The comparison is carried out for a model of a second-generation supersonic transport for this vehicle. The MOCM’s potential in evaluating alternative flight control system laws is discussed as well.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer’s disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC50= 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).

Abstract: The electrical properties (permittivity, dissipation factor, and electrical conductivity) of the Li0.03Na0.97TayNb1 – yO3(y= 0.1–0.7) ferroelectric solid solutions with a perovskite structure have been studied. In the temperature range of 290–830 K, the investigated solid solutions undergo three phase transitions. The phase transitions are strongly smeared with increasing tantalum concentration. The Curie temperatures have been established, and it has been shown that an increase in the tantalum concentration leads to a decrease in the Curie temperature. The static electrical conductivity of the Li0.03Na0.97TayNb1 –yO3(y= 0.1–0.7) ferroelectric solid solutions and the activation enthalpies of charge carriers have been determined.

Superconductivity in a nitride of the MAX-phase family was reported by A.D. Bortolozo et al. in Ti2InN (a = 0.3074 nm, c = 1.3975 nm) with a transition temperature of 7.3 K. In this study, we report on Ti2InN MAX phase-based samples (with up to 94 wt.% of Ti2InN) synthesized by several methods, which, unfortunately, did not comply with bulk superconductivity of this compound. The Ti2InN materials were synthesized from Ti2InN precursor powder of 93–95 wt.% purity (obtained by the method proposed by (Bortolozo et al., 2010)) according to the following routes: (1) at 130 bar of N2, leading to 54 wt.% of Ti2InN (a = 0.3076(1), c = 1.4012(5) nm); (2) in a sealed quartz ampoule in Ar, (88.5 wt.% Ti2InN, a = 0.3076(1), c = 1.4012(4) nm); (3) by spark plasma sintering (SPS) in contact with hBN at 45 MPa (94 wt.% Ti2InN, a = 0.3077(7), c = 1.4021(5) nm), and (4) by high quasihydrostatic pressure - high temperature sintering (HP-HT) in contact with hBN at 4 GPa (83.5 wt.% Ti2InN, a = 0.3075(3), c = 1.4017(5) nm). Despite all the manufactured samples demonstrated superconducting behaviour with Tc (onset) near 5 K and the samples prepared by SPS and HP-HT methods were highly dense, a very broad magnetic transition (ac susceptibility) not saturating down to 2 K has been observed. No macroscopic Meissner phase was established and the magnetization was far too weak to evidence bulk superconductivity of the entire sample and hence of Ti2InN. However, a superconducting gap of about 1.2–2.1 mV was derived from point-contact spectroscopy at some areas of HP-HT sintered samples. The dispersed crystalline admixture grains of TiN phase in Ti2InN matrices of our samples or a metallic In-alloy are most probable candidates for the superconducting phase in our materials.

Microscale organisms and specialized motile cells use protein-based spring-like responsive structures to sense, grasp and move. Rendering this biomechanical transduction functionality in an artificial micromachine for applications in single-cell manipulations is challenging due to the need for a bio-applicable nanoscale spring system with a large and programmable strain response to piconewton-scale forces. Here we present three-dimensional nanofabrication and monolithic integration, based on an acrylic elastomer photoresist, of a magnetic spring system with quantifiable compliance sensitive to 0.5 pN, constructed with customized elasticity and magnetization distributions at the nanoscale. We demonstrate the effective design programmability of these ‘picospring’ ensembles as energy transduction mechanisms for the integrated construction of customized soft micromachines, with onboard sensing and actuation functions at the single-cell scale for microrobotic grasping and locomotion. The integration of active soft springs into three-dimensional nanofabrication offers an avenue to create biocompatible soft microrobots for non-disruptive interactions with biological entities.

Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL. In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment.

Parameters to adapt individual treatment strategies for patients with pancreatic ductal adenocarcinoma (PDAC) are urgently needed. The present study aimed to evaluate body composition parameters as predictors of overall survival (OS) in PDAC patients. Measurements of body composition parameters were performed on computed tomography scans at diagnosis. Height‐standardized and Body Mass Index‐ and sex‐adjusted regression formulas deriving cut‐offs from a healthy population were used. The Kaplan‐Meier method with the log‐rank test was performed for survival analysis. Independent prognostic factors were identified with uni‐ and multivariable Cox regression analyses. In total, 354 patients were analyzed. In a multivariable Cox model, besides tumor stage and resection status, only myosteatosis (HR 1.53; 95% CI 1.10–2.14, p= 0.01) was an independent prognostic factor of OS among body composition parameters. Subgroup analyses revealed that the prognostic impact of myosteatosis was higher in patients ≤68 years of age, with advanced tumor stages and patients without curative intended resection. The analysis of one of the largest Caucasian cohorts to date, demonstrated myosteatosis to be an independent prognostic factor of OS in PDAC. To improve outcomes, prospective trials aiming to investigate the utility of an early assessment of myosteatosis with subsequent intervention by dieticians, sports medicine physicians, and physiotherapists are warranted. The present study aimed to evaluate body composition parameters as predictors of overall survival (OS) in patients with pancreatic ductal adenocarcinoma. Measurements of body composition parameters were performed on computed tomography scans at diagnosis. In a multivariable Cox model myosteatosis was an independent prognostic factor of OS among body composition parameters. However, prospective trials aiming to investigate the utility of early assessment of myosteatosis with subsequent intervention by dieticians, sports medicine physicians, and physiotherapists are warranted.

During tight manoeuvres, twin-screw ships equipped with two rudders located in the propeller slip stream experience a fairly large imbalance in the hydrodynamic loads on the propeller and rudders. To investigate the phenomenon of rudder asymmetric load in some depth, manoeuvring experiments based on a free-running model were set up in which the kinematics of the model, the forces on the rudder and the stock moment were recorded. In parallel, with the aim of obtaining an exact estimation of free-stream characteristics of the rudder blade, corresponding wind tunnel experiments were also performed. Based on the results of this investigation, an analysis of the interaction effects within the hull-propeller-rudder system was performed and some conclusions were drawn.

Single-particle cryogenic electron microscopy (cryo-EM) allows reconstruction of high-resolution structures of proteins in different conformations. Protein function often involves transient functional conformations, which can be resolved using time-resolved cryo-EM (trEM). In trEM, reactions are arrested after a defined delay time by rapid vitrification of protein solution on the EM grid. Despite the increasing interest in trEM among the cryo-EM community, making trEM samples with a time resolution below 100 ms remains challenging. Here we report the design and the realization of a time-resolved cryo-plunger that combines a droplet-based microfluidic mixer with a laser-induced generator of microjets that allows rapid reaction initiation and plunge-freezing of cryo-EM grids. Using this approach, a time resolution of 5 ms was achieved and the protein density map was reconstructed to a resolution of 2.1 Å. trEM experiments on GroEL:GroES chaperonin complex resolved the kinetics of the complex formation and visualized putative short-lived conformations of GroEL–ATP complex.

Abstract: Forward osmosis is considered as an emerging technology that can compete with existing methods of desalination, purification, and concentration of natural and wastewater on the global water market. This review presents possible applications of forward osmosis, technological schemes, and the most striking case studies. The issues of forward osmosis membranes development and improvement, composition and regeneration of draw solutions, membrane fouling are considered. Special attention is paid to the problems arising during forward osmosis operation as well as to energy and economic assessment of new technology. Conclusions are drawn about the status of the commercial implementation of forward osmosis and the main barriers that stand in the way of its development.

In the work, a fine powder of GdNb0.9Ta0.1O4-mixed gadolinium tantalum niobate activated with rare earth (REE) cations (Sm3+, Eu3+, Tb3+and Er3+) was obtained by sol–gel synthesis. The evolution of the powder from amorphous to crystalline form was also studied in the work. The evolution was studied by synchronous thermal and X-ray analysis. The phase composition and structure of the resulting Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4powders were analyzed in detail. Ceramic samples of the Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4polycomponent solid solution were prepared from the sol–gel synthesized powder using traditional ceramic technology. The phase composition and characteristics of the structure of individual phases of the Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4ceramic solid solution was determined by full-profile analysis of XRD patterns of polycrystals. We established that incorporation of REE (Tb, Er, Eu, Sm) into the gadolinium site in GdNb0.9Ta0.1O4solid solution leads to various distortions of the corresponding polyhedra. Note that the distortion degree in this case is much greater than the distortion of the initial GdNbO4structure. The photoluminescent (PL) properties of the Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4solid solution were studied in the visible wavelength range. Analysis of literature and our own data revealed: electronic relaxation pathways in Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4ceramics can be different depending on the energy of the exciting radiation. Excitation by the 376 nm line leads to internal energy conversion over 4fn–4fnlevels of REE cations (Sm3+, Eu3+, Tb3+and Er3+). The energy transfer between the Nb4+–O−–Ta4+–O−groups and REE is maximal in this case, while the radiation of the matrix from Nb4+–O−–Ta4+–O−emission centers is minimal. Upon excitation in the near-UV range (376 nm), Gd3+cations do not participate in the energy transfer between the matrix and 4fn–4fnlevels of REE dopants. The maximum PL of Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4ceramics is observed in the green–red region of the spectrum from 5D0–7F2and 4G5/2–6H7/2transitions of Eu3+and Sm3+. The emission is maximal at ~ 612 nm; it corresponds to the 5D0–7F2electric dipole transition of the Eu3+cation. We established that the efficiency of energy transfer between the matrix and doping REE cations for Gd0.96Eu0.01Sm0.01Tb0.01Er0.01Nb0.9Ta0.1O4ceramics strongly depends on the energy of the exciting radiation.

Phase-change superlattices with nanometer thin sublayers are promising for low-power phase-change memory (PCM) on rigid and flexible platforms. However, the thermodynamics of the phase transition in such nanoscale superlattices remain unexplored, especially at ultrafast scanning rates, which is crucial for our fundamental understanding of superlattice-based PCM. Here, we probe the phase transition of Sb2Te3(ST)/Ge2Sb2Te5(GST) superlattices using nanocalorimetry with a monolayer sensitivity (∼1 Å) and a fast scanning rate (105K/s). For a 2/1.8 nm/nm Sb2Te3/GST superlattice, we observe an endothermic melting transition with an ∼240 °C decrease in temperature and an ∼8-fold decrease in enthalpy compared to those for the melting of GST, providing key thermodynamic insights into the low-power switching of superlattice-based PCM. Nanocalorimetry measurements for Sb2Te3alone demonstrate an intrinsic premelting similar to the unique phase transition of superlattices, thus revealing a critical role of the Sb2Te3sublayer within our superlattices. These results advance our understanding of superlattices for energy-efficient data storage and computing.

Biomolecular condensates (BMCs) are crucial for cellular organization and function, and their dysregulation is linked to neurological, oncologic and inflammatory diseases. This highlights the need for advanced investigative tools leading to targeted BMC therapeutics. To address this need, Nereid Therapeutics uses Corelet™ technology and an automated high-throughput screening (HTS) platform to precisely quantify phase separation events and identify BMC modulators for previously undruggable targets. Hundreds of thousands of small molecules have been screened utilizing Corelet technology, yielding small molecule BMC-modulating compounds which serve as the basis for the development of targeted therapies for diseases with high unmet need.

Fear, an emotion ingrained through evolutionary adaptation, triggers protective responses to ward off threats. Yet, in some instances, the neural networks tied to fear can lead to psychosomatic ailments and behavioural issues, including the maladaptive type. This study aims to hypothesize about fear, probing its neurophysiological traits and its impact on cognitive-emotional facets of the psyche. A systematic review of theoretical literature was conducted, utilizing PubMed and Scopus databases. Comparative analysis, abstraction, and synthesis methods were employed, and 34 sources that met the inclusion criteria analysed. Our findings highlight the pivotal role fear plays in the human psyche, potentially serving as the foundation for all emotions, feelings, and states experienced by individuals. Treating fear and related anxiety disorders poses challenges due to the recurrence of fear-based memories, which perpetuate negative symptoms in patients. Various techniques, like hypnotherapy, cognitive behavioural therapy, and exposure therapy, are actively employed with these patients. However, none offer a universal solution, necessitating personalized approaches to address individual fears. MindChat may be promising in therapeutic settings to address fear responses without altering cognition or fostering avoidance behaviour, but empirical evidence supporting its efficacy is limited, and further research is needed to validate its effectiveness. The utilization of fear as a potent tool in engaging with the psyche underscores the potential value of this study for psychotherapists in clinical practice and professionals in affective neurobiology and behavioural psychology. It redirects attention toward fear’s significance, urging a deeper exploration in future research endeavours.

Enveloped viruses, such as flaviviruses and coronaviruses, are pathogens of significant medical concern that cause severe infections in humans. Some photosensitizers are known to possess virucidal activity against enveloped viruses, targeting their lipid bilayer. Here we report a series of halogenated difluoroboron-dipyrromethene (BODIPYs) photosensitizers with strong virus-inactivating activity. Our structure–activity relationship analysis revealed that BODIPY scaffolds with a heavy halogen atom demonstrate significant efficacy against both tick-borne encephalitis virus (TBEV; Flaviviridaefamily) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridaefamily) along with high singlet oxygen quantum yields. Moreover, select compounds also inactivated other enveloped viruses, such as herpes simplex virus type 1 and monkeypox virus. The nature and length of the alkyl side chain notably influenced the virus-inactivating activity of BODIPY molecules. Furthermore, molecular dynamics studies highlighted the critical importance of the positioning of the chromophore moiety within the lipid bilayer. As membrane-targeting photosensitizers, BODIPYs interact directly with virus particles, causing damage to the viral envelope membranes. Thus, TBEV pretreated with BODIPY was completely noninfective for lab mice. Consequently, BODIPY-based photosensitizers hold potential either as broad-spectrum virus-inactivating antivirals against a variety of phylogenetically unrelated enveloped viruses or as potent inactivators of viruses for the development of vaccines for preventing life-threatening emerging viral diseases.

Für komplexe Fabrikplanungsprojekte, wie z. B. die Neu- oder Erweiterungsplanung, ist in der Regel ein umfangreicher Kapitalbedarf erforderlich, der die finanziellen Unternehmensmittel stark belastet. Für die richtige Beurteilung der Wirtschaftlichkeit eines Fabrikplanungsprojektes ist eine Abschätzung der Baukosten von existenzieller Bedeutung. Oftmals ist unklar, wie die strategischen Ziele sowie kontextbasierten Rahmenbedingungen (z. B. Grundstück oder Fabrikbedarfe) die Baukosten beeinflussen. Dabei ist Letzteres für gewöhnlich ein ausschlaggebendes Auswahlkriterium. Dieser Beitrag stellt ein methodisches Vorgehen vor, mit dessen Hilfe Fabrikziele durch bauliche Maßnahmen konkretisiert und mit den Bedarfen der Fabrik in eine gemeinsame Beschreibungsbasis gebracht werden können. Das Ziel ist die Abschätzung von Baukosten zur Durchführung einer Vorstudie auf Grundlage vordefinierter Baustandards.

Electrocatalytic CO2reduction reaction (CO2RR) is greatly facilitated by Au surfaces. However, large fractions of underlying Au atoms are generally unused during the catalytic reaction, which limits mass activity. Herein, we report a strategy for preparing efficient electrocatalysts with high mass activities by the atomic-level transplantation of Au active sites into a Ni4nanocluster (NC). While the Ni4NC exclusively produces H2, the Au-transplanted NC selectively produces CO over H2. The origin of the contrasting selectivity observed for this NC is investigated by combining operando and theoretical studies, which reveal that while the Ni sites are almost completely blocked by the CO intermediate in both NCs, the Au sites act as active sites for CO2-to-CO electroreduction. The Au-transplanted NC exhibits a remarkable turnover frequency and mass activity for CO production (206 molCO/molNC/s and 25,228 A/gAu, respectively, at an overpotential of 0.32 V) and high durability toward the CO2RR over 25 h.

A series of small (7–12 mer) amphipathic cationic peptides were designed and synthesized to create short helical peptides with broad-range bactericidal activity and selectivity toward the bacterial cells. The analysis identified a lead 12-mer peptide 8bwith broad-spectrum activity against Gram-positive (MIC = 3.1–6.2 μg/mL) and Gram-negative (MIC = 6.2–12.5 μg/mL) bacteria and selectivity toward prokaryotic versus eukaryotic cells (HC50= 280 μg/mL, >75% cell viability at 150 μg/mL). The rapid membranolytic action of 8bwas demonstrated by a calcein dye leakage assay and confirmed using scanning electron microscopy. According to circular dichroism and NMR spectroscopy, the peptides have an irregular spatial structure in water. A lipid bilayer induced an amphipathic helix only in 12-mer peptides, including 8b. Molecular dynamics simulations provided detailed information about the interaction of 8band its closest analogues with bacterial and mammalian membranes and revealed the roles of particular amino acids in the activity and selectivity of peptides.

Super-resolution microscopy is widely used in the development of novel antimicrobial testing in vitro. In the presented work, a scanning protocol was developed by the method of scanning ion-conducting microscopy (SICM), which makes it possible to study microorganisms without rigid fixation and in saline, obtaining an index map of nanosized structures. The effect of azole and echinocandins drugs on the morphology and mechanical properties of Candida parapsilosis yeast was studied. The findings are consistent with previously proposed drug mechanisms and reports that have examined antifungal agents using AFM, SEM, and TEM. We have shown that the SICM method is capable of scanning and detecting the nanomechanical properties of yeast non-invasively.

Defrost sensors are a crucial element for proper functioning of the pharmaceutical cold chain. In this paper, the self-assembled peptide-based hydrogels were used to construct a sensitive defrost sensor for the transportation and storage of medications and biomaterials. The turbidity of the peptide hydrogel was employed as a marker of the temperature regime. The gelation kinetics under different conditions was studied to detect various stages of hydrogel structural transitions aimed at tuning the system properties. The developed sensor can be stored at room temperature for a long period, irreversibly indicates whether the product has been thawed, and can be adjusted to a specific temperature range and detection time.

Abstract—: Oxidation of tris(3-fluorophenyl)antimony with tert-butyl hydroperoxide in the presence of 2-methylcarboranylcarboxylic acid leads to the formation of tris(3-fluorophenyl)antimony bis(2-methylcarboranylcarboxylate) (1), whose structural features were established by X-ray diffraction analysis. According to X-ray diffraction analysis carried out at 293 K using a D8 Quest Bruker automatic four-circle diffractometer (two-coordinate CCD detector, MoKαradiation, λ = 0.71073 Å, graphite monochromator), crystals are characterized as follows: C26H38B20F3O4Sb, M 809.52; monoclinic syngony, symmetry group С2/c; cell parameters: a= 19.050(13) Å, b= 14.441(9) Å, c= 14.568(9) Å; α = 90°, β = 98.51(2)°, γ = 90°; V= 3964(4) Å3; Z= 4; crystal size 0.8 × 0.55 × 0.29 mm; reflection index intervals –25 ≤ h≤ 25, –18 ≤ k≤ 18, –18 ≤ l≤ 19; total reflections 37 401; independent reflections 4709; Rint0.0545; GOOF1.108; R1= 0.0578, wR2= 0.1482; residual electron density –0.59/1.09 e /Å3. According to the X-ray diffraction data, the antimony atoms in the molecules of compound 1have a distorted trigonal-bipyramidal coordination with oxygen atoms of the carboxylate ligands in axial positions. The Sb–C bonds (2.104(4)–2.114(8) Å) are shorter than the Sb–O distances (2.113(3) Å), the OSbО axial angle is 178.48(15)°, the CSbC angles are 109.7(2)°, 118.4(2)°, and 131.8(3)°. The significant increase in one of the angles is associated with the cis-conformation of carboxylate ligands relative to the equatorial plane. There is a propeller conformation of aryl ligands with respect to the equatorial plane [C3]. Structure 1contains intramolecular Sb···O=C contacts between the antimony and oxygen atoms of the carbonyl groups of the carboxylate ligands, which are 3.089(3) Å. The formation of a spatial network in the crystal of compound 1is due to the presence of weak hydrogen bonds carboxylate ligands and fluorine aryl ligands with the participation of boron atoms: B···H (3.19 Å) and F···B (3.45 Å). Complete tables of atomic coordinates, bond lengths, and bond angles have been deposited with the Cambridge Crystallographic Data Center (no. 2178731; deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk/data_request/cif).

Having in mind that the tourism industry has been seen as highly complex and competitive, which is driven also by the rapid change in technology, the paper examines the perceptions and practices of Macedonian travel agencies that have intentions to boost their international exposure and find new strategies to perform. Data were collected from 96 employees’ responses to identify external macro and competitive environment factors as well as to further investigate of the patterns and perceptions regarding their international strategy practices. Two considerations are taken into the discussion. What travel agencies might do in view of changes in the global environment and in view of its abilities and what entry mode is most suitable. Hence, the findings from the paper support the notion for greater internationalization and for encouraging travel agencies to establish new strategic alliances. Also, it can provide relevant and useful information for the policy makers which can be used for improving the overall tourism country internationalization efforts.

A large amount of circumstantial evidence has accumulated suggesting that Toll-like receptor (TLR) signals are involved in driving chronic lymphocytic leukemia (CLL) cell proliferation, but direct in vivo evidence for this is still lacking. We have now further addressed this possibility by pharmacologically inhibiting or genetically inactivating the TLR pathway in murine CLL and human Richter syndrome (RS) patient-derived xenograft (PDX) cells. Surprisingly, we show that pharmacologic inhibition of TLR signaling by treatment with an IRAK1/4 inhibitor delays the growth of the transplanted malignant cells in recipient mice, but genetic inactivation of the same pathway by CRISPR/Cas9-mediated disruption of IRAK4 or its proximal adaptor MyD88 has no effect. We further show that treatment with the IRAK1/4 inhibitor results in depletion of macrophages and demonstrate that these cells can support the survival and enhance the proliferation of both murine Eμ-TCL1 leukemia and human RS cells. We also show that genetic disruption of the B-cell receptor (BCR) by CRISPR/Cas9 editing of the immunoglobulin M constant region gene inhibits the growth of human RS-PDX cells in vivo, consistent with our previous finding with murine Eμ-TCL1 leukemia cells. Finally, we show that genetic disruption of IRAK4 does not result in negative selection of human CLL cell lines xenografted in immunodeficient mice. The obtained data suggest that TLR signals are unlikely to represent a major driver of CLL/RS cell proliferation and provide further evidence that signals from macrophages and the BCR promote the growth and survival of CLL and RS cells in vivo.

•Human Richter syndrome and murine CLL cells receive growth-promoting signals from B-cell receptor but not from Toll-like receptors in vivo.•Depletion of macrophages results in reduced growth of murine CLL and human Richter syndrome cells in vivo.