Feasibility and Cardiometabolic Effects of Time-Restricted Eating in Patients with Metabolic Syndrome.

Metabolic syndrome (MetS) and a prolonged daily eating window (EW) are associated with circadian rhythm disruption and increased cardiometabolic risk. Misalignment between circadian timing system and daily rhythms of food intake adversely impacts metabolic regulatory mechanisms and cardiovascular function. Restricting the daily EW by imposing an eating-fasting cycle through time-restricted eating (TRE) can restore robust circadian rhythms, support cellular metabolism, and improve cardiometabolic health. The aim of this study was to assess a feasibility of 12-week TRE intervention with self-selected 10 h EW and effects of TRE on EW duration, cardiometabolic outcomes, daily rhythms of behavior, and wellbeing in Polish patients with MetS and EW ≥ 14 h/day. Dietary intake was monitored with a validated myCircadianClock application (mCC app). Adherence to TRE defined as the proportion of days recorded with mCC app in which participants satisfied 10-h TRE was the primary outcome. A total of 26 patients (aged 45 ± 13 years, 62% women, 3.3 ± 0.5 MetS criteria, EW 14 ± 1.5 h/day) were enrolled. Coexistence of increased waist circumference (WC) (96% of patients), elevated fasting plasma glucose (FPG) (77%), and elevated blood pressure (BP) (69%) was the most common MetS pattern (50%). TRE intervention (mean duration of 81.6 ± 12.6 days) led to reducing daily EW by 28% (p < 0.0001). Adherence to TRE was 87 ± 13%. Adherence to logging food intake on mCC app during TRE was 70 ± 27%. Post TRE, a decrease in body weight (2%, 1.7 ± 3.6 kg, p = 0.026), body mass index (BMI) (1%, 0.5 ± 1.2 kg/m2, p = 0.027), WC (2%, 2.5 ± 3.9 cm, p = 0.003), systolic BP (4%, 4.8 ± 9.0 mmHg, p = 0.012), FPG (4%, 3.8 ± 6.9 mg/dL, p = 0.037), glycated hemoglobin (4%, 0.2 ± 0.4%, p = 0.011), mean fasting glucose level from continuous glucose monitor (CGM) (4%, 4.0 ± 6.1 mg/dL, p = 0.002), and sleepiness score (25%, 1.9 ± 3.2 points, p = 0043) were observed. A significant decrease in body weight (2%), BMI (2%), WC (3%), mean CGM fasting glucose (6%), sleepiness score (27%), and depression score (60%) was found in patients with mean post-TRE EW ≤ 10 h/day (58% of total), and not in patients with EW > 10 h/day. Adherence to TRE was higher in patients with post-TRE EW ≤ 10 h/day vs. patients with EW > 10 h/day (94 ± 6% vs. 77 ± 14%, p = 0.003). Our findings indicate that 10-h TRE was feasible in the European MetS population. TRE resulted in reducing daily EW and improved cardiometabolic outcomes and wellbeing in patients with MetS and prolonged EW. Use of the mCC app can aid in implementing TRE. This pilot clinical trial provides exploratory data that are a basis for a large-scale randomized controlled trial to determine the efficacy and sustainability of TRE for reducing cardiometabolic risks in MetS populations. Further research is needed to investigate the mechanisms of TRE effects, including its impact on circadian rhythm disruption.

Nonlinear Analysis of the Hand and Foot Force-Time Profiles in the Four Competitive Swimming Strokes.

Human locomotion on water depends on the force produced by the swimmer to propel the body forward. Performance of highly complex motor tasks like swimming can yield minor variations that only nonlinear analysis can be sensitive enough to detect. The purpose of the present study was to examine the nonlinear properties of the hand/feet forces and describe their variations across the four competitive swimming strokes performing segmental and full-body swimming. Swimmers performed all-out bouts of 25 m in the four swimming strokes, swimming the full-body stroke, with the arm-pull only and with the leg kicking only. Hand/foot force and swimming velocity were measured. The Higuchi's fractal dimension (HFD) and sample entropy (SampEn) were used for the nonlinear analysis of force and velocity. Both the arm-pull and leg kicking alone were found to produce similar peak and mean hand/foot forces as swimming the full-body stroke. Hand force was more complex in breaststroke and butterfly stroke; conversely, kicking conditions were more complex in front crawl and backstroke. Moreover, the arm-pull and kicking alone tended to be more complex (higher HFD) but more predictable (lower SampEn) than while swimming the full-body stroke. There was no loss of force production from segmental swimming to the full-body counterpart. In conclusion, the number of segments in action influences the nonlinear behavior of the force produced and, when combining the four limbs, the complexity of the hand/foot force tends to decrease.

Quantitative measurement of mammographic density in breast-tissue explants using portable NMR: Precision and accuracy.

PURPOSE: Single-sided portable NMR (pNMR) has previously been demonstrated to be suitable for quantification of mammographic density (MD) in excised breast tissue samples. Here we investigate the precision and accuracy of pNMR measurements of MD ex vivo as compared with the gold standards. METHODS: Forty-five breast-tissue explants from 9 prophylactic mastectomy patients were measured. The relative tissue water content was taken as the MD-equivalent quantity. In each sample, the water content was measured using some combination of three pNMR techniques (apparent T2, diffusion, and T1 measurements) and two gold-standard techniques (computed microtomography [µCT] and hematoxylin and eosin [H&E] histology). Pairwise correlation plots and Bland-Altman analysis were used to quantify the degree of agreement between pNMR techniques and the gold standards. RESULTS: Relative water content measured from both apparent T2 relaxation spectra, and diffusion decays exhibited strong correlation with the H&E and µCT results. Bland-Altman analysis yielded average bias values of -0.4, -2.6, 2.6, and 2.8 water percentage points (pp) and 95% confidence intervals of 13.1, 7.5, 11.2, and 11.8 pp for the H&E - T2, µCT - T2, H&E - diffusion, and µCT - diffusion comparison pairs, respectively. T1-based measurements were found to be less reliable, with the Bland-Altman confidence intervals of 27.7 and 33.0 pp when compared with H&E and µCT, respectively. CONCLUSION: Apparent T2-based and diffusion-based pNMR measurements enable quantification of MD in breast-tissue explants with the precision of approximately 10 pp and accuracy of approximately 3 pp or better, making pNMR a promising measurement modality for radiation-free quantification of MD.

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic lipid and carbohydrate metabolism.

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Acute administration of a CSF1-Fc fusion protein to mice led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilization of body fat. The impacts of CSF1 on macrophage abundance, liver size, and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, and control of liver-to-body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilization, without changes in appetence, which may have novel implications for managing metabolic syndrome.NEW & NOTEWORTHY CSF1 administration expands tissue macrophages, which transforms systemic metabolism. CSF1 drives fat mobilization and glucose uptake to support liver growth. The effects of CSF1 are independent of normal hormonal metabolic regulation. The effects of CSF1 are rapidly reversible, restoring homeostatic body composition. CSF1-dependent macrophages and liver size are coupled in a dynamic equilibrium.

Associative pyridinium electrolytes for air-tolerant redox flow batteries.

Pyridinium electrolytes are promising candidates for flow-battery-based energy storage1-4. However, the mechanisms underlying both their charge-discharge processes and overall cycling stability remain poorly understood. Here we probe the redox behaviour of pyridinium electrolytes under representative flow battery conditions, offering insights into air tolerance of batteries containing these electrolytes while providing a universal physico-chemical descriptor of their reversibility. Leveraging a synthetic library of extended bispyridinium compounds, we track their performance over a wide range of potentials and identify the singlet-triplet free energy gap as a descriptor that successfully predicts the onset of previously unidentified capacity fade mechanisms. Using coupled operando nuclear magnetic resonance and electron paramagnetic resonance spectroscopies5,6, we explain the redox behaviour of these electrolytes and determine the presence of two distinct regimes (narrow and wide energy gaps) of electrochemical performance. In both regimes, we tie capacity fade to the formation of free radical species, and further show that π-dimerization plays a decisive role in suppressing reactivity between these radicals and trace impurities such as dissolved oxygen. Our findings stand in direct contrast to prevailing views surrounding the role of π-dimers in redox flow batteries1,4,7-11 and enable us to efficiently mitigate capacity fade from oxygen even on prolonged (days) exposure to air. These insights pave the way to new electrolyte systems, in which reactivity of reduced species is controlled by their propensity for intra- and intermolecular pairing of free radicals, enabling operation in air.

Oxygen uptake kinetics and biological age in relation to pulling force and 400-m front crawl performance in young swimmers.

Background: The study aimed to assess differences in the biological age (BA) of 13-year-old swimmers and show their ability, as biologically younger-late mature or older-early mature, to develop fast 60-s oxygen uptake (V˙O2) kinetics and tethered swimming strength. Furthermore, the interplay between swimming strength, V˙O2, and 400-m front crawl race performance was examined. Methods: The study involved 36 competitive young male swimmers (metrical age: 12.9 ± 0.56 years). Depending on BA examination, the group was divided into early-mature (BA: 15.8 ± 1.18 years, n = 13) and late-mature (BA: 12.9 ± 0.60 years, n = 23) participants, especially for the purpose of comparing tethered swimming indices, i.e., average values of force (F ave) and V˙O2 (breath-by-breath analysis) kinetic indices, measured simultaneously in 1-min tethered front crawl swimming. From the 400-m racing stroke rate, stroke length kinematics was retrieved. Results: In the 1-min tethered front crawl test, early-mature swimmers obtained higher results of absolute values of V˙O2 and F ave. Conversely, when V˙O2 was present relatively to body mass and pulling force (in ml∙min-1∙kg-1∙N-1), late-mature swimmers showed higher O2 relative usage. Late-mature swimmers generally exhibited a slower increase in V˙O2 during the first 30 s of 60 s. V˙O2, F ave, BA, and basic swimming kinematic stroke length were significantly interrelated and influenced 400-m swimming performance. Conclusion: The 1-min tethered swimming test revealed significant differences in the homogeneous calendar age/heterogeneous BA group of swimmers. These were distinguished by the higher level of V˙O2 kinetics and pulling force in early-mature individuals and lower efficiency per unit of body mass per unit of force aerobic system in late-mature peers. The higher V˙O2 kinetics and tethered swimming force were further translated into 400-m front crawl speed and stroke length kinematics.

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer.

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele had reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

A Spiky Silver-Iron Oxide Nanoparticle for Highly Efficient Targeted Photothermal Therapy and Multimodal Imaging of Thrombosis.

Thrombosis and its complications are responsible for 30% of annual deaths. Limitations of methods for diagnosing and treating thrombosis highlight the need for improvements. Agents that provide simultaneous diagnostic and therapeutic activities (theranostics) are paramount for an accurate diagnosis and rapid treatment. In this study, silver-iron oxide nanoparticles (AgIONPs) are developed for highly efficient targeted photothermal therapy and imaging of thrombosis. Small iron oxide nanoparticles are employed as seeding agents for the generation of a new class of spiky silver nanoparticles with strong absorbance in the near-infrared range. The AgIONPs are biofunctionalized with binding ligands for targeting thrombi. Photoacoustic and fluorescence imaging demonstrate the highly specific binding of AgIONPs to the thrombus when functionalized with a single chain antibody targeting activated platelets. Photothermal thrombolysis in vivo shows an increase in the temperature of thrombi and a full restoration of blood flow for targeted group but not in the non-targeted group. Thrombolysis from targeted groups is significantly improved (p < 0.0001) in comparison to the standard thrombolytic used in the clinic. Assays show no apparent side effects of AgIONPs. Altogether, this work suggests that AgIONPs are potential theranostic agents for thrombosis.

Body composition and anthropometrics of young male swimmers in relation to the tethered swimming and kinematics of 100-m front crawl race.

BACKGROUND: The aim was to analyze the relationship of body mass and predicted muscle mass of body segments on swimming kinematics and tethered swimming indices, and further assess the influence of those indices on 100-m front crawl performance of adolescent male swimmers. METHODS: In 19 volunteer swimmers (age: 13.5±0.44 years, height: 168.6±7.77 cm, body mass: 56.9±10.57 kg), the predicted muscle mass of body segments was assessed with bioelectrical impedance analysis. The kinematic indices of swimming (stroke rate - SR, stroke length - SL, and stroke index - SI) were calculated from a video recording of a 100-m front crawl race. The strength indices (maximum and average value of force, average impulse per single cycle, force decline) were collected in a 30-second front crawl tethered swimming test. RESULTS: The average tethered swimming force was positively correlated with surface swimming speed (0.505; P≤0.05). Indices of SL, SI were influenced by average impulse per single cycle (0.58, 0.55; P≤0.05), and further the SI was strongly correlated with most specified speed indices of the 100-m race (0.59; P≤0.05). CONCLUSIONS: It can be stated that the ability of force development in a single stroke, owing to strong interrelation with SI, is a good predictor in talent identification among young swimmers.

V ˙ O 2 kinetics and tethered strength influence the 200-m front crawl stroke kinematics and speed in young male swimmers.

Background: The aim of this research was to examine the relationship between the fast component of oxygen consumption developed in 1-min V ˙ O 2 and force indices both measured in tethered swimming test and to assess the influence of the gathered indices on speed and swimming kinematics in 200-m front crawl race. Methods: Forty-eight male swimmers (aged 13.5 ± 0.9 years old) participated in this study. Testing included 1) 1-min all-out front crawl tethered swimming while oxygen consumption (breath by breath) and tethered forces were measured, 2) 200-m front crawl race-like swimming featuring kinematic analysis, and 3) biological age (BA) examination. Results: During the 1-min all-out tethered swimming test, a linear increase in oxygen consumption was observed. There were moderate to high partial correlations between particular periods of seconds in the 1-min V ˙ O 2 : 31-60, 41-60, and 51-60 and F max, F ave , and I ave of tethered swimming, while 41-60 and 51-60 V ˙ O 2 were moderately to highly interrelated with all the swimming speed indices and SI. The swimming speed indices significantly interplayed with SL, SI, F max, F ave , and I ave . Partial correlations were computed with BA control. Conclusion: The ability of reaching a high level of V ˙ O 2 fast is essential for a swimmer's energy production at short- and middle-distance events. Reaching a high level of V ˙ O 2 significantly determines tethered strength and swimming kinematics. The level of V ˙ O 2 influences the maintenance of a proper pulling force and the stroke technique of front crawl swimming in young male swimmers.

CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy.

Rationale: An antibody-drug conjugate (ADC) is a targeted therapy consisting of a cytotoxic payload that is linked to an antibody which targets a protein enriched on malignant cells. Multiple ADCs are currently used clinically as anti-cancer agents significantly improving patient survival. Herein, we evaluated the rationale of targeting the cell surface oncoreceptor CUB domain-containing protein 1 (CDCP1) using ADCs and assessed the efficacy of CDCP1-directed ADCs against a range of malignant tumors. Methods: CDCP1 mRNA expression was evaluated using large transcriptomic datasets of normal/tumor samples for 23 types of cancer and 15 other normal organs, and CDCP1 protein expression was examined in 34 normal tissues, >300 samples from six types of cancer, and in 49 cancer cell lines. A recombinant human/mouse chimeric anti-CDCP1 antibody (ch10D7) was labelled with 89Zirconium or monomethyl auristatin E (MMAE) and tested in multiple pre-clinical cancer models including 36 cancer cell lines and three mouse xenograft models. Results: Analysis of CDCP1 expression indicates elevated CDCP1 expression in the majority of the cancers and restricted expression in normal human tissues. Antibody ch10D7 demonstrates a high affinity and specificity for CDCP1 inducing cell signalling via Src accompanied by rapid internalization of ch10D7/CDCP1 complexes in cancer cells. 89Zirconium-labelled ch10D7 accumulates in CDCP1 expressing cells enabling detection of pancreatic cancer xenografts in mice by PET imaging. Cytotoxicity of MMAE-labelled ch10D7 against kidney, colorectal, lung, ovarian, pancreatic and prostate cancer cells in vitro, correlates with the level of CDCP1 on the plasma membrane. ch10D7-MMAE displays robust anti-tumor effects against mouse xenograft models of pancreatic, colorectal and ovarian cancer. Conclusion: CDCP1 directed imaging agents will be useful for selecting cancer patients for personalized treatment with cytotoxin-loaded CDCP1 targeting agents including antibody-drug conjugates.

Effect of dentine site on resin and cement adaptation tested using X-ray and electron microscopy to evaluate bond durability and adhesive interfaces.

Glass ionomer (GI) cements and self-etch (SE) or universal adhesives after etching (ER) adapt variably with dentine. Dentine characteristics vary with depth (deep/shallow), location (central/peripheral), and microscopic site (intertubular/peritubular). To directly compare adhesion to dentine, non-destructive imaging and testing are required. Here, GI, ER, and SE adapted at different dentine depths, locations, and sites were investigated using micro-CT, xenon plasma focused ion beam scanning electron microscopy (Xe PFIB-SEM), and energy dispersive X-ray spectroscopy (EDS). Extracted molars were prepared to deep or shallow slices and treated with the three adhesives. Micro-CT was used to compare changes to air volume gaps, following thermocycling, and statistically analysed using a quantile regression model and Fisher's exact test. The three adhesives performed similarly across dentine depths and locations, yet no change or overall increases and decreases in gaps at all dentine depths and locations were measured. The Xe PFIB-SEM-milled dentine-adhesive interfaces facilitated high-resolution characterization, and element profiling revealed variations across the tooth-material interfaces. Dentine depth and location had no impact on adhesive durability, although microscopic differences were observed. Here we demonstrate how micro-CT and Xe PFIB-SEM can be used to compare variable dental materials without complex multi-stage specimen preparation to minimize artefacts.

Supramolecular encapsulation of redox-active monomers to enable free-radical polymerisation.

Extended polymeric structures based on redox-active species are of great interest in emerging technologies related to energy conversion and storage. However, redox-active monomers tend to inhibit radical polymerisation processes and hence, increase polydispersity and reduce the average molecular weight of the resultant polymers. Here, we demonstrate that styrenic viologens, which do not undergo radical polymerisation effectively on their own, can be readily copolymerised in the presence of cucurbit[n]uril (CB[n]) macrocycles. The presented strategy relies on pre-encapsulation of the viologen monomers within the molecular cavities of the CB[n] macrocycle. Upon polymerisation, the molecular weight of the resultant polymer was found to be an order of magnitude higher and the polydispersity reduced 5-fold. The mechanism responsible for this enhancement was unveiled through comprehensive spectroscopic and electrochemical studies. A combination of solubilisation/stabilisation of reduced viologen species as well as protection of the parent viologens against reduction gives rise to the higher molar masses and reduced polydispersities. The presented study highlights the potential of CB[n]-based host-guest chemistry to control both the redox behavior of monomers as well as the kinetics of their radical polymerisation, which will open up new opportunities across myriad fields.

Tuning the local chemical environment of ZnSe quantum dots with dithiols towards photocatalytic CO2 reduction.

Sunlight-driven CO2 reduction to renewable fuels is a promising strategy towards a closed carbon cycle in a circular economy. For that purpose, colloidal quantum dots (QDs) have emerged as a versatile light absorber platform that offers many possibilities for surface modification strategies. Considerable attention has been focused on tailoring the local chemical environment of the catalytic site for CO2 reduction with chemical functionalities ranging from amino acids to amines, imidazolium, pyridines, and others. Here we show that dithiols, a class of organic compounds previously unexplored in the context of CO2 reduction, can enhance photocatalytic CO2 reduction on ZnSe QDs. A short dithiol (1,2-ethanedithiol) activates the QD surface for CO2 reduction accompanied by a suppression of the competing H2 evolution reaction. In contrast, in the presence of an immobilized Ni(cyclam) co-catalyst, a longer dithiol (1,6-hexanedithiol) accelerates CO2 reduction. 1H-NMR spectroscopy studies of the dithiol-QD surface interactions reveal a strong affinity of the dithiols for the QD surface accompanied by a solvation sphere governed by hydrophobic interactions. Control experiments with a series of dithiol analogues (monothiol, mercaptoalcohol) render the hydrophobic chemical environment unlikely as the sole contribution of the enhancement of CO2 reduction. Density functional theory (DFT) calculations provide a framework to rationalize the observed dithiol length dependent activity through the analysis of the non-covalent interactions between the dangling thiol moiety and the CO2 reduction intermediates at the catalytic site. This work therefore introduces dithiol capping ligands as a straightforward means to enhance CO2 reduction catalysis on both bare and co-catalyst modified QDs by engineering the particle's chemical environment.

On-Resin Recognition of Aromatic Oligopeptides and Proteins through Host-Enhanced Heterodimerization.

Peptide dimerization is ubiquitous in natural protein conjugates and artificial self-assemblies. A major challenge in artificial systems remains achieving quantitative peptide heterodimerization, critical for next-generation biomolecular purification and formulation of therapeutics. Here, we employ a synthetic host to simultaneously encapsulate an aromatic and a noncanonical l-perfluorophenylalanine-containing peptide through embedded polar-π interactions, constructing an unprecedented series of heteropeptide dimers. To demonstrate the utility, this heteropeptide dimerization strategy was applied toward on-resin recognition of N-terminal aromatic residues in peptides as well as insulin, both exhibiting high recycling efficiency (>95%). This research unveils a generic approach to exploit quantitative heteropeptide dimers for the design of supramolecular (bio)systems.

Correlations between Crawl Kinematics and Speed with Morphologic, Functional, and Anaerobic Parameters in Competitive Swimmers.

The purpose of this study was to examine the relationship between a unique complex of predictors and 100 m front crawl race kinematics and swimming speed. In 28 male competitive swimmers (age: 19.6 ± 2.59 years), the following groups of predictors were assessed: (a) the morphologic, (b) the functional upper limb range of motion, and (c) the anaerobic indices of arm-cranking and a series of countermovement jumps. The Pearson product-moment correlation coefficient was calculated to distinguish the predictors and the swimming results. The main finding was that the indices of the power (arm-cranking) and the work (countermovement jump) generated in the anaerobic tests showed a significant and higher correlation with stroke length and stroke index than total body length, upper limb range of motion, or hand and forearm surface area. These results were obtained in accordance with the high swimming economy index relation to clear surface swimming speed. This study reveals that the strength generated by the limbs may represent a predictor of swimming kinematics in a 100 m front crawl performance.

Therapeutic potential of macrophage colony-stimulating factor in chronic liver disease.

Resident and recruited macrophages control the development and proliferation of the liver. We have previously shown in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here, we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, using a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodelling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.

Neuropilin-1 is over-expressed in claudin-low breast cancer and promotes tumor progression through acquisition of stem cell characteristics and RAS/MAPK pathway activation.

BACKGROUND: Triple-negative breast cancers (TNBC) have a relatively poor prognosis and responses to targeted therapies. Between 25 and 39% of TNBCs are claudin-low, a poorly differentiated subtype enriched for mesenchymal, stem cell and mitogen-activated signaling pathways. We investigated the role of the cell-surface co-receptor NRP1 in the biology of claudin-low TNBC. METHODS: The clinical prognostic value of NRP1 was determined by Kaplan-Meier analysis. GSVA analysis of METABRIC and Oslo2 transcriptomics datasets was used to correlate NRP1 expression with claudin-low gene signature scores. NRP1 siRNA knockdown was performed in MDA-MB-231, BT-549, SUM159 and Hs578T claudin-low cells and proliferation and viability measured by live cell imaging and DNA quantification. In SUM159 orthotopic xenograft models using NSG mice, NRP1 was suppressed by shRNA knockdown or systemic treatment with the NRP1-targeted monoclonal antibody Vesencumab. NRP1-mediated signaling pathways were interrogated by protein array and Western blotting. RESULTS: High NRP1 expression was associated with shorter relapse- and metastasis-free survival specifically in ER-negative BrCa cohorts. NRP1 was over-expressed specifically in claudin-low clinical samples and cell lines, and NRP1 knockdown reduced proliferation of claudin-low cells and prolonged survival in a claudin-low orthotopic xenograft model. NRP1 inhibition suppressed expression of the mesenchymal and stem cell markers ZEB1 and ITGA6, respectively, compromised spheroid-initiating capacity and exerted potent anti-tumor effects on claudin-low orthotopic xenografts (12.8-fold reduction in endpoint tumor volume). NRP1 was required to maintain maximal RAS/MAPK signaling via EGFR and PDGFR, a hallmark of claudin-low tumors. CONCLUSIONS: These data implicate NRP1 in the aggressive phenotype of claudin-low breast cancer and offer a novel targeted therapeutic approach to this poor prognosis subtype.

Study of talented young male swimmers - scientific approach to the kinematic and physiological predictors of 400-m front crawl race.

PURPOSE: The purpose of this study was to assess the influence of physiological and kinematic predictors on 400-m front crawl race in young male swimmers and to consider the interrelation between them. METHODS: Nineteen male swimmers took part in this study (age: 13.5 ± 0.44 years, height: 168.6 ± 7.77 cm, body mass: 56.9 ± 10.57 kg). Measurements of physiological parameters were conducted using expired air analyzer (Start 2000 MES, Poland) during step-test in water flume. Kinematic indices were computed while analyzing video recording of 400-m front crawl race. To check for possible influence of biological age (BA) diversity in studied group, partial correlation with age control was computed. RESULTS: Swimming to exhaustion in water flume defined as speed at maximum oxygen uptake and anaerobic threshold ( VVO2 max and VAT) occurred to be strongly positively correlated with 400-m race speed. Speed in surface swimming zones (Vsurface) was related to ability of kinematics adjustment and significantly correlated with stroke index (SI). Vsurface at the beginning and the end of the race, i.e., at 1st, 7th and 8th lap interplayed with stroke rate (SR) measured at corresponding laps. CONCLUSIONS: Our study showed that 400-m front crawl performance of young male swimmers is strongly dependent on swimming efficiency developed with aerobic conditioning. Significant role of proper pacing strategy was also identified, which indicates that race pace training should be implemented.

From a Well-Defined Organozinc Precursor to Diverse Luminescent Coordination Polymers Based on Zn(II)-Quinolinate Building Units Interconnected by Mixed Ligand Systems.

Introduction of photoactive building blocks into mixed-ligand coordination polymers appears to be a promising way to produce new advanced luminescent materials. However, rational design and self-assembly of the multi-component supramolecular systems is challenging from both a conceptual and synthetic perspective. Here, we report exploratory studies that investigate the potential of [Zn(q)2]2[tBuZn(OH)]2 complex (q = deprotonated 8-hydroxyquinoline) as an organozinc precursor as well as a mixed-ligand synthetic strategy for the preparation of new luminescent coordination polymers (CPs). As a result we present three new 2D mixed-ligand Zn(II)-quinolinate coordination polymers which are based on various zinc quinolinate secondary building units interconnected by two different organic linker types, i.e., deprotonated 4,4'-oxybisbenzoic acid (H2obc) as a flexible dicarboxylate linker and/or selected bipyridines (bipy). Remarkably, using the title organozinc precursors in a combination with H2obc and 4,4'-bipyridine, a novel molecular zinc quinolinate building unit, [Zn4(q)6(bipy)2(obc)2], was obtained which self-assembled into a chain-type hydrogen-bonded network. The application of the organometallic precursor allowed for its direct reaction with the selected ligands at ambient temperature, avoiding the use of both solvothermal conditions and additional base reagents. In turn, the reaction involving Zn(NO3)2, as a classical inorganic precursor, in a combination with H2obc and bipy led to a novel 1D coordination polymer [Zn2(q)2(NO3)2(bipy)]. While the presence of H2obc was essential for the formation of this coordination polymer, this ditopic linker was not incorporated into the isolated product, which indicates its templating behavior. The reported compounds were characterized by single-crystal and powder X-ray diffraction, elemental analysis as well as UV-Vis and photoluminescence spectroscopy.