This work indicate that the MN-Ms may be a promising embolic agent for TCE applications for advanced liver cancer.Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are mainly found in marine fish oils and commercially available fish oil supplements. Several studies have documented that n-3 PUFAs can reduce the risk of cardiovascular diseases through anti-inflammatory, anti-thrombotic, and anti-atherosclerotic properties. Notably, regulation of vascular tone is one of the most important bases of cardiovascular health and especially for maintaining blood pressure within optimal physiological ranges. Recent clinical and animal studies indicate an association between n-3 PUFAs and vascular functions. In this regard, many clinical trials and basic experimental studies have been conducted so far to investigate the influence of n-3 PUFAs on vascular tone. In this review, we have summarized the results obtained from both clinical and basic studies that evaluated the effect of n-3 PUFAs under physiological and pathological conditions. Moreover, we also focus on verifying the underlying basic molecular mechanism of n-3 PUFAs on the vascular system.The dispersive behavior of three different amorphous solid dispersion (ASD) formulations of the poorly soluble ABT-199 (Venetoclax) were studied in aqueous and biomimetic media and spontaneously forming supramolecular associates and particles analysed. To this end, the aqueous dispersions were fractionated into a submicron (colloidal) and micrometer-sized particle-fraction by bench-top centrifugation. The submicron fraction was characterized by Asymmetric Flow Field-Flow Fractionation in conjunction with Multi-angle Laser Light Scattering (AF4-MALLS), Dynamic Light Scattering (DLS) and zeta potential analysis. The micron particle fraction was characterized by Single Particle Optical Sensing (SPOS) and light microscopy. Furthermore, drug contents were monitored in terms of total dispersed drug and apparently dissolved drug in the submicron fraction. Despite the fact, that all three formulations showed decent dispersive behavior with almost the complete drug content rapidly dispersed, substantial differences were identified between two of the formulations and the third one ABT-199/12 and ABT-199/20 showed pronounced precipitation of the drug in form of micrometer particles, a phenomenon described as glass liquid phase separation (GLPS) and only a marginal fraction of the drug was found in the submicron-fraction, i.e. associated with 3 to 4 different supramolecular assemblies (micelles), irrespective whether buffer or fasted state simulated intestinal fluid (FaSSIF) were used as dispersion media. In contrast, ABT-199/40 showed pronounced formation of a wide variety of supramolecular assemblies (micelles) along with substantial association of the drug with all of these, but reduced glass liquid phase separation.Irbesartan is a poorly soluble BCS class II compound with weak acidic properties. After oral administration, dual peaks are noted in its concentration (C) – time (t) profile, a phenomenon that may be attributed to enterohepatic recirculation, gastric emptying and/or other absorption complexities related to its pH- and buffer capacity-dependent dissolution behavior. A population pharmacokinetic model, encompassing delay differential equations, was found the most appropriate approach to describe dual peaks in irbesartan’s C-t profiles. Parameters estimated were the absorption rate constant in the central compartment (ka = 0.304 h-1), the constant time delay between the administration and the absorption (T=1.68 h), the apparent volume of distribution of the central (V1/F = 13.8 L) and peripheral (V2/F = 85.8 L) compartment, the apparent clearance from the central compartment (CL/F = 13.5 L/h), and the inter-compartmental clearance (Q/F = 17.7 L/h). Using simulations, it was made evident that changing the time delay results in significant changes of peak plasma concentrations but not of its blood pressure-lowering effect. In conclusion, delay differential equations may be useful to model dual peaks arising from absorption complexities, while changes of the time delay that reflect physiological processes that take place before absorption may have significant implications in proving bioequivalence.The presence, biosynthesis and functional role of sterols in the green microalga Haematococcus pluvialis remain poorly understood. In this work we studied the effect of high-light (HL) stress on sterol synthesis in H. pluvialis UTEX 2505 cells. HL stress induced the synthesis of sterols in parallel with that of triacylglycerides (TAG), giving rise to the synthesis of cholesterol over that of phytosterols. Blockage of the carotenogenic 1-deoxy-D-xylulose 5-phosphate (MEP) pathway is shown to be involved in HL-induced sterol synthesis. In addition, high irradiance exposure induced MEP- and fatty acid (FA)-biosynthetic transcripts. The pharmacological inhibition of these pathways suggests a possible feedback regulation of sterol and FA homeostasis. Finally, both lipid classes proved crucial to the adequate photosynthetic performance of H. pluvialis grown under HL intensity stress. Our findings reveal new insights into H. pluvialis lipid metabolism that contribute to the development of value-added bioproducts from microalgae.

Elevations in pancreatic α-cell intracellular Ca

([Ca

]

) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca

handling is unknown. Lactate enters cells through monocarboxylate transporters (MCTs) and is also produced during glycolysis by lactate dehydrogenase A (LDHA), an enzyme expressed in α-cells. As lactate activates ATP-sensitive K

(K

) channels in cardiomyocytes, lactate may also modulate α-cell K

. Therefore, this study investigated how lactate signaling controls α-cell Ca

handling and GCG secretion.

Mouse and human islets were used in combination with confocal microscopy, electrophysiology, GCG immunoassays, and fluorescent thallium flux assays to assess α-cell Ca

handling, V

, K

currents, and GCG secretion.

Lactate-inhibited mouse (75±25%) and human (47±9%) α-cell [Ca

]

fluctuations only under low-glucose conditions (1mM) but had no effect on β- or δ-cells [Ca

]

. Glyburide inhibition of K

channels restorethin α-cells and/or elevated in serum could serve as important modulators of α-cell function.Latent sensitization is a model of chronic pain in which a persistent state of pain hypersensitivity is suppressed by opioid receptors, as evidenced by the ability of opioid antagonists to induce a period of mechanical allodynia. Our objective was to determine if substance P and its neurokinin 1 receptor (NK1R) mediate the maintenance of latent sensitization. Latent sensitization was induced by injecting rats in the hindpaw with complete Freund’s adjuvant (CFA), or by tibial spared nerve injury (SNI). When responses to von Frey filaments returned to baseline (day 28), the rats were injected intrathecally with saline or the NK1R antagonist RP67580, followed 15 min later by intrathecal naltrexone. In both pain models, the saline-injected rats developed allodynia for 2 h after naltrexone, but not the RP67580-injected rats. Saline or RP67580 were injected daily for two more days. Five days later (day 35), naltrexone was injected intrathecally. Again, the saline-injected rats, but not the RP67580-injected rats, developed allodynia in response to naltrexone. To determine if there is sustained activation of NK1Rs during latent sensitization, NK1R internalization was measured in lamina I neurons in rats injected in the paw with saline or CFA, and then injected intrathecally with saline or naltrexone on day 28. The rats injected with CFA had a small amount of NK1R internalization that was significantly higher than in the saline-injected rats. Naltrexone increased NK1R internalization in the CFA-injected rats but nor in the saline-injected rats. Therefore, sustained activation of NK1Rs maintains pain hypersensitivity during latent sensitization.Accumulating evidence suggests a widespread role of serotonin 5-HT7 receptors (5-HT7Rs) in the physiology of cognitive and affective processing. However, we still lack insights into 5-HT7R electrophysiology. Studies analyzing the 5-HT7R-mediated changes in CA1 pyramidal neuron activity revealed that 5-HT7R activation leads to the opening of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCNs). However, our group and others have shown that CA1 pyramidal cells increase their excitability following 5-HT7R activation, an effect which cannot be explained by HCN channel opening. This suggests a different ionic mechanism might be responsible. To investigate this, we performed whole-cell patch clamp recordings of CA1 pyramidal cells in rat brain slices. It was found that acute 5-HT7R activation increased membrane excitability and decreased spiking latency. Both effects were blocked by a selective 5-HT7R antagonist. Spike latency in CA1 pyramidal cells is known to be regulated by transient outward voltage-dependent A-type potassium channels. Subsequent voltage clamp recordings revealed that acute 5-HT7R activation inhibited A-type potassium currents. Pharmacological block of Kv4.2/4.3 potassium channel subunits prevented the 5-HT7R agonist-induced changes in excitability and spiking latency, whereas blocking HCN channels had no influence on these effects. Taken together, the results reveal an ionic mechanism previously not known to be associated with 5-HT7R activation. Inhibition of A-type potassium channels can fully account for increased CA1 pyramidal cell excitability after 5-HT7R activation. These results can help explain a number of behavioral and physiological findings and will hopefully lead to a better understanding of 5-HT7 receptor signaling in health and disease.Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam. Apremilast prolonged rotarod ataxia induced by zolpidem, propofol, and loreclezole, shortened recovery from diazepam, but had no effect on ataxia induced by gaboxadol or etomidate. The PKA inhibitor H-89 blocked apremilast’s ability to prolong the sedative-hypnotic effects of ethanol, gaboxadol, and propofol and to prolong ethanol- and propofol-induced ataxia. H-89 also blocked apremilast’s ability to shorten the sedative-hypnotic and ataxic effects of diazepam. The β1-specific antagonist, salicylidene salicylhydrazide (SCS), produced faster recovery from ethanol- and diazepam-induced ataxia, but did not alter propofol- or etomidate-induced ataxia. SCS shortened the sedative-hypnotic effects of ethanol and diazepam but not of propofol. In Xenopus oocytes, a phosphomimetic (aspartate) mutation at the PKA phosphorylation site in β1 subunits decreased the maximal GABA current in receptors containing α1 or α3, but not α2 subunits. In contrast, phosphomimetic mutations at PKA sites in β3 subunits increased the maximal GABA current in receptors containing α1 or α2, but not α3 subunits. The GABA potency and allosteric modulation by ethanol, propofol, etomidate, zolpidem, flunitrazepam, or diazepam were not altered by these mutations. We propose a model whereby apremilast increases PKA-mediated phosphorylation of β1-and β3-containing GABAA receptors and selectively alters acute tolerance to ethanol and GABAergic drugs.While glia are essential for regulating the homeostasis in the normal brain, their dysfunction contributes to neurodegeneration in many brain diseases, including Parkinson’s disease (PD). Recent studies have identified that PD-associated genes are expressed in glial cells as well as neurons and have crucial roles in microglia and astrocytes. Here, we discuss the role of microglia and astrocytes dysfunction in relation to PD-linked mutations and their implications in PD pathogenesis. A better understanding of microglia and astrocyte functions in PD may provide insights into neurodegeneration and novel therapeutic approaches for PD.As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/-) mice, purinergic control of phagocytosis was only affected in male Nf1+/- mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/-, microglia. These defects resulted from Nf1+/- male-specific defects in cyclic AMP regulation, rather than from changes in purinergic receptor expression. Cyclic AMP elevation by phosphodiesterase blockade restored the male Nf1+/- microglia defects in P2Y-dependent membrane currents and process motility. Taken together, these data establish a sex-by-genotype interaction important to microglia function in the adult mouse brain.Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness of these symptoms has occurred during the last decade, their underlying neuropathophysiological circuitry remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these health issues. Recent studies have examined the neuropathological status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with neurodegenerative diseases. A deeper understanding of these mechanisms will provide not only a better understanding of disease neuro-pathophysiology, but also hold the promise for developing effective and mechanisms-based therapies.

To determine if an oxalate strip reduced fluid flow in dentine samples and whether this reduction was maintained following a 14 day intra-oral period.

Dentine tubule fluid flow was measured by a modified Pashley cell in 40 acid-etched dentine discs 1 mm thick, diameter >10 mm, with an acquired pellicle, pre-equilibrated with Hartmann’s solution and conditioned by toothbrushing, pre and post treatment (10 min) with an oxalate (3.14 %) gel strip or no treatment. One control and one test sample were exposed in-situ for 14 days to the oral environment in 20 healthy adult volunteers, and fluid flow re-measured. The appliance containing the two samples was removed for brushing with water after mealtimes when the participant brushed their teeth and for a 2 min daily soak in chlorhexidine.

Fluid flow rate was reduced significantly immediately following treatment with the oxalate strip compared to baseline flow rate by 58 %. Following 14 days in-situ oral environment phase, a significant further reduction in achieving and maintaining dentine tubule occlusion when participants had no dietary restrictions. This demonstrates the suitability of the oxalate strip for the treatment of patients suffering from dentine hypersensitivity pain.

This retrospective, single-center, practice-based cohort study aimed to analyze the longevity of direct fiber reinforced composite fixed partial dentures (DFRC-FPD) and to analyze factors influencing their survival and success.

Within one private practice 100 DFRC-FPD were directly applied. The preparation of a proximal cavity was limited to abutment teeth with an existing filling (minimal-invasive approach). All intact enamel surfaces were preserved (micro-invasive approach). DFRC-FPD were reinforced by fiber-splints with semi polymer network matrices (Everstick C + B©). At the last follow-up DFRC-FPD were considered successful if they were still in function without any need of therapy. DFRC-FPD were considered as survived if they were repaired or replaced. Multi-level Cox proportional hazard models were used to evaluate the association between clinical factors and time.

Within a mean follow-up period (range) of 53 (2-109) months 7 bridges did not survive (cumulative survival rate 93%) and further 24 box-shaped proximal cavity was prepared.In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRβ. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.A new series of uracil analogues-1,2,4-oxadiazole hybrid derivatives were synthesized by a new, simple, and efficient method using for the first time HAP-SO3H as an heterogenous acid catalyst for the condensation and cyclization between amidoxime and aldehyde. The new derivatives were characterized by HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques. The synthesized 1,2,4-oxadiazole hybrids were evaluated for their cytotoxic activity in five human cancer cell lines melanoma (A-375), fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). Data showed that compounds 22 and 23 were potent cytotoxic agents against HT-1080 and MFC-7 cells with IC50 inferior to 1 µM. The possible mechanism of apoptosis induction by the derivatives was investigated using Annexin V staining, caspase-3/7 activity, mitochondrial membrane potential measurement, and analysis cell cycle progression. The compound 22 induced apoptosis through caspase-3/7 activation and S-phase arrest in HT-1080 and A549 cells. The molecular docking showed that compound 22 activated the caspase-3 by forming a stable protein-ligand complex.Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.Our sphingosine kinase inhibitor (SKI) optimization studies originated with the optimization of the SKI-I chemotype by replacement of the substituted benzyl rings with substituted phenyl rings giving rise to the discovery of SKI-178. We have recently reported that SKI-178 is a dual-targeted inhibitor of both sphingosine kinase isoforms (SphK1/2) and a microtubule disrupting agent (MDA). In mechanism-of-action studies, we have shown that these two separate actions synergize to induce cancer cell death in acute myeloid leukemia (AML) cell and animal models. Owning to the effectiveness of SKI-178, we sought to further refine the chemotype while maintaining „on-target” SKI and MDA activities. Herein, we modified the „linker region” between the substituted phenyl rings of SKI-178 through a structure guided approach. These studies have yielded the discovery of an SKI-178 congener, SKI-349, with log-fold enhancements in both SphK inhibition and cytotoxic potency. Importantly, SKI-349 also demonstrates log-fold improvements in therapeutic efficacy in a retro-viral transduction model of MLL-AF9 AML as compared to previous studies with SKI-178. Together, our results strengthen the hypothesis that simultaneous targeting of the sphingosine kinases (SphK1/2) and the induction of mitotic spindle assembly checkpoint arrest, via microtubule disruption, might be an effective therapeutic strategy for hematological malignancies including AML.As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed, synthesized and characterized by 1H NMR, 13C HNMR, and HRMS spectra. These compounds, with an IC50 range of 5.0-205.1 nM, showed superior inhibitory activity against FAK. Two compounds, [18F]Q-2 and [18F]Q-4, with respective IC50 values of 5.0 nM and 21.6 nM, were labelled by 18F, accompanied by evaluation of their biodistributions. For [18F]Q-2, at 30 min post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood, tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated that [18F]Q-2 is a potential PET tracer for tumour diagnosis.The shells of the Pacific oyster Crassostrea gigas contain calcite crystals with three types of microstructures prismatic, chalky, and foliated layers. Many shell matrix proteins were annotated from the shells of C. gigas; however, it is unclear which SMPs play important roles in their shell mineralization. The matrix proteins have never been reported from the chalky layer. In this study, we identified a chalky layer-derived EGF-like domain-containing protein (CgELC) from the chalky layer of C. gigas shells. The gene sequence of the CgELC was encoded under CGI_ 10,017,544 of the C. gigas genome database. Only peptide fragments in the N-terminal region of CGI_ 10,017,544 were detected by LC-MS/MS analyses, suggesting that CGI_ 10,017,544 was digested at the predicted protease digestion dibasic site by post-translational modification to become a mature CgELC protein. We produced three types of CgELC recombinant proteins, namely, the full length CgELC, as well as the N-terminal and C-terminal parts of CgELC (CgELC-N or -C, respectively), for in vitro crystallization experiments. In the presence of these recombinant proteins, the aggregation of polycrystalline calcite was observed. Some fibrous organic components seemed to be incorporated into the calcite crystals in the presence of the r-CgELC protein. We also noted different features in the crystallization between CgELC-N and CgELC-C; some crystals were inhibited crystal plane formation and contained many columnar prisms inside the crystals (CgELC-N) and formed numerous holes on their surfaces (CgELC-C). These results suggest that CgELC is involved in crystal aggregation and incorporated into calcite crystals.It is shown how serial block-face electron microscopy (SBEM) of insulin-secreting β-cells in wild-type mouse pancreatic islets of Langerhans can be used to determine maturation times of secretory granules. Although SBEM captures the β-cell structure at a snapshot in time, the observed ultrastructure can be considered representative of a dynamic equilibrium state of the cells since the pancreatic islets are maintained in culture in approximate homeostasis. It was found that 7.2 ± 1.2% (±st. dev.) of the β-cell volume is composed of secretory granule dense-cores exhibiting angular shapes surrounded by wide (typically ≳100 nm) electron-lucent halos. These organelles are identified as mature granules that store insulin for regulated release through the plasma membrane, with a release time of 96 ± 12 h, as previously obtained from pulsed 35S-radiolabeling of cysteine and methionine. Analysis of β-cell 3D volumes reveals a subpopulation of secretory organelles without electron-lucent halos, identified as immature secretory granules. Another subpopulation of secretory granules is found with thin (typically ≲30 nm) electron-lucent halos, which are attributed to immature granules that are transforming from proinsulin to insulin by action of prohormone convertases. From the volume ratio of proinsulin in the immature granules to insulin in the mature granules, we estimate that the newly formed immature granules remain in morphologically-defined immature states for an average time of 135 ± 14 min, and the immature transforming granules for an average time of 130 ± 17 min.The mineralized extracellular matrix of bone is an organic-inorganic nanocomposite consisting primarily of carbonated hydroxyapatite, fibrous type I collagen, noncollagenous proteins, proteoglycans, and diverse biomolecules such as pyrophosphate and citrate. While much is now known about the mineralization-regulating role of pyrophosphate, less is known about the function of citrate. In order to assess the effect of negatively charged citrate on collagen mineralization, citrate-functionalized, bone osteoid-mimicking dense collagen gels were exposed to simulated body fluid for up to 7 days to examine the multiscale evolution of intra- and interfibrillar collagen mineralization. Here, we show by increases in methylene blue staining that the net negative charge of collagen can be substantially augmented through citrate functionalization. Structural and compositional analyses by transmission and scanning electron microscopy (including X-ray microanalysis and electron diffraction), and atomic force microscopy, all demonstrated that citrate-functionalized collagen fibrils underwent extensive intrafibrillar mineralization within 12 h in simulated body fluid. Time-resolved, high-resolution transmission electron microscopy confirmed the temporal evolution of intrafibrillar mineralization of single collagen fibrils. Longer exposure to simulated body fluid resulted in additional interfibrillar mineralization, all through an amorphous-to-crystalline transformation towards apatite (assessed by X-ray diffraction and attenuated total reflection-Fourier-transform infrared spectroscopy). Calcium deposition assays indicated a citrate concentration-dependent temporal increase in mineralization, and micro-computed tomography confirmed that >80 vol% of the collagen in the gels was mineralized by day 7. In conclusion, citrate effectively induces mesoscale intra- and interfibrillar collagen mineralization, a finding that advances our understanding of the role of citrate in mineralized tissues.Akkermansia muciniphila is a beneficial microorganism colonized in the human gut that can reverse many intestinal metabolic-related diseases. Amuc_1100 is an outer-membrane protein of A. muciniphila. Oral administration of Amuc_1100 can reduce fat mass development, insulin resistance, and dyslipidemia in mice and activated the toll-like receptor 2 (TLR2) to regulate the immune response of the host, but the molecular mechanism remains unclear. Here we report the crystal structure of the extramembranous domain of Amuc_1100, which consists of a four-stranded antiparallel β-sheet and four α-helices. Two C-terminal helices and the four-stranded antiparallel β-sheet formed two „αββ” motifs and constituted the core domain, which shared a similar fold with type IV pili and type II Secretion system protein. Although the full-length of the extramembranous domain of Amuc_1100 existed as a monomer in solution, they formed trimer in the crystal. Elimination of the N-terminal coiled-coil helix α1 led to dimerization of Amuc_1100 both in solution and in crystal, indicating that the oligomeric state of Amuc_1100 was variable and could be influenced by α1. In addition, we identified that Amuc_1100 could directly bind human TLR2 (hTRL2) in vitro, suggesting that Amuc_1100 may serve as a new ligand for hTLR2. Dimerization of Amuc_1100 improved its hTLR2-binding affinity, suggesting that the α1-truncated Amuc_1100 could be a beneficial candidate for the development of A. muciniphila related drugs.Tailed bacteriophages are one of the most widespread biological entities on Earth. Their singular structures, such as spikes or fibers are of special interest given their potential use in a wide range of biotechnological applications. In particular, the long fibers present at the termini of the T4 phage tail have been studied in detail and are important for host recognition and adsorption. Although significant progress has been made in elucidating structural mechanisms of model phages, the high-resolution structural description of the vast population of marine phages is still unexplored. In this context, we present here the crystal structure of C24, a putative receptor-binding tip-like protein from Bizionia argentinensis JUB59, a psychrotolerant bacterium isolated from the marine surface waters of Potter Cove, Antarctica. The structure resembles the receptor-binding tip from the bacteriophage T4 long tail fiber yet showing marked differences in its domain organization, size, sequence identity and metal binding nature. We confirmed the viral origin of C24 by induction experiments using mitomycin C. Our results reveal the presence of a novel uncharacterized prophage in the genome of B. argentinensis JUB59, whose morphology is compatible with the order Caudovirales and that carries the nucleotide sequence of C24 in its genome. This work provides valuable information to expand our current knowledge on the viral machinery prevalent in the oceans.Angiogenesis after intracerebral hemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. Hypoxia-inducible factor 2α (HIF-2α) is an important angiogenic regulator and exhibits protective effects in several neurological diseases; however, its role in ICH has not yet been reported. Hence, in the present study, we explored whether HIF-2α reduces ICH injury by promoting angiogenesis. In addition, we explored the role of the vascular endothelial growth factor (VEGF)/Notch pathway in HIF-2α-mediated angiogenesis. We injected 50 μL of autologous blood taken from the femoral artery into the right striatum of healthy male adult Sprague-Dawley rats to create an autologous-blood-induced rat model of ICH. Lentiviral vectors were injected to both overexpress and knock down HIF-2α expression. VEGF receptor 2 (VEGFR2) and Notch-specific inhibitors were injected intraperitoneally to block VEGFR2- and Notch-mediated signaling after lentiviral injections. Our data showed that HIF-2α overexpression reduced neurological-damage scores and brain-water content, suggesting it had a protective effect on ICH injury. In addition, overexpression of HIF-2α promoted angiogenesis, increased focal cerebral blood flow (CBF), and reduced neuronal damage, whereas HIF-2α knockdown resulted in the opposite effects. Furthermore, we found that HIF-2α-mediated angiogenesis was blocked by a Notch-specific inhibitor. Likewise, the HIF-2α-mediated increase in phospho-VEGFR-2, cleaved-Notch1 and Notch1 expression was reversed via a VEGFR2-specific inhibitor. Taken together, our results indicate that HIF-2α promotes angiogenesis via the VEGF/Notch pathway to attenuate ICH injury. Moreover, our findings may contribute to the development of a novel strategy for alleviating ICH injury via HIF-2α-mediated upregulation of angiogenesis.In the visual decoding domain, the most difficult task is the visual reconstruction aimed at reconstructing the presented visual stimuli given the corresponding human brain activity monitored by functional magnetic resonance imaging (fMRI), especially when reconstructing viewed natural images. Recent research regarded the visual reconstruction as the conditional image generation on fMRI voxels and started to use the generative adversarial networks (GANs) to design computational models for this task. Despite the great improvement in previous GAN-based methods, the fidelity and naturalness of the reconstructed images are still unsatisfactory, the reasons include the small number of fMRI data samples and the instability of GAN training. In this study, we propose a new GAN-based Bayesian visual reconstruction model (GAN-BVRM) to avoid the contradiction between naturalness and fidelity in current GAN-based methods. GAN-BVRM is composed of a classifier to decode the categories from fMRI data, a pre-trained conditional generator of the distinguished BigGAN to generate natural images of the specified categories, and a set of encoding models and an evaluator to evaluate the generated images. Composed of neural networks, GAN-BVRM is fully differentiable and can directly generate the reconstructed images by iteratively updating the noise input vector through backpropagation to fit the fMRI voxels. In this process, the decoded categories and encoding models are responsible for the semantic and detailed contents of the reconstructed images, respectively. Experimental results revealed that GAN-BVRM improved the fidelity and naturalness, which validated the advantage of the combining of GANs and Bayesian manner for visual reconstruction.Motor imagery (MI) ability is highly subjective, as indicated by the individual scores of the MIQ-3 questionnaire, and poor imagers compensate for the difficulty in performing MI with larger cerebral activations, as demonstrated by MI studies involving hands/limbs. In order to identify general, task-independent MI ability correlates, 16 volunteers were stratified with MIQ-3. The scores in the kinaesthetic (K) and 1st-person visual (V) perspectives were associated with EEG patterns obtained during K-MI and V-MI of the same complex MIQ-3 movements during these MI tasks (Spearman’s correlation, significance at less then 0.05, SnPM corrected). EEG measures were relative to rest (relaxation, closed eyes), and based on six electrode clusters both for band spectral content and connectivity (Granger causality). Lower K-MI ability was associated with greater theta decreases during tasks in fronto-central clusters and greater inward information flow to prefrontal clusters for theta, high alpha and beta bands. On the other hand, power band relative decreases were associated with V-MI ability in fronto-central clusters for low alpha and left fronto-central and both centro-parietal clusters for beta bands. The results thus suggest different computational mechanisms for MI-V and MI-K. The association between low alpha/beta desynchronization and V-MIQ scores and between theta changes and K-MIQ scores suggest a cognitive effort with greater cerebral activation in participants with lower V-MI ability. The association between information flow to prefrontal hub and K-MI ability suggest the need for a continuous update of information to support MI-related executive functions in subjects with poor K-MI ability.Exposure to environmental contaminants is a public health concern. However, pre-clinical studies that examine the impact of pesticides at low-dose and the long-term consequences are uncommon. Here, C57BL6/j male and female mice were daily fed from weaning and up to 12 months, corresponding to early-childhood into middle-age in humans, using chow pellets containing a cocktail of pesticides at tolerable daily intake levels. We found that 12 months of dietary exposure to pesticides was associated with a moderate perenchymal or perivascular astrogliosis in specific hippocampal sub-regions. The expression of platelet-derived growth factor receptor beta was modified at the perivascular level. Examination of Iba1+ microglial cells did not reveal sizeable changes. Concomitantly to astrogliosis, spontaneous spatial memory and sociability were modified in males at 12 months of dietary exposure to pesticides. Telemetry electrocorticograhic explorations ruled out the presence of epileptiform activity or theta-gamma wave modifications in these conditions. Long-term pesticides impacted the periphery where the hepatic P450 metabolic cytochromes Cyp4a14 and Cyp4a10 were significantly upregulated in male and female mice during the 12 months of exposure. The expression of β-oxidation genes, such as Acox1, Cpt1a and Eci, was also significantly increased in male and female mice in response to pesticides. Collectively, our results indicate that a life-long exposure to a pesticide cocktail elicits sex-dependent, spatio-temporally restricted brain modifications and significant activation of P450 pathways in the periphery. These brain-peripheral adjustments are discussed as time or age-dependent vulnerability elements.Cyclin E is a key factor for S phase entry, and deregulation of Cyclin E results in developmental defects and tumors. Therefore, proper cycling of Cyclin E is crucial for normal growth. Here we found that transcription factors Apontic (Apt) and E2f1 cooperate to induce cyclin E in Drosophila. Functional binding motifs of Apt and E2f1 are clustered in the first intron of Drosophila cyclin E and directly contribute to the cyclin E transcription. Knockout of apt and e2f1 together abolished Cyclin E expression. Furthermore, Apt up-regulates Retinoblastoma family protein 1 (Rbf1) for proper chromatin compaction, which is known to repress cyclin E. Notably, Apt-dependent up-regulation of Cyclin E and Rbf1 is evolutionarily conserved in mammalian cells. Our findings reveal a unique mechanism underlying the induction and subsequent decline of Cyclin E expression.

Chronic granulomatous disease (CGD) is characterized by defective microbial killing due to mutations affecting subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Definitive genetic identification of disease subtypes may be delayed or not readily available.

Sought to investigate the role of intracellular staining of NADPH oxidase enzyme subunits in predicting the respective genetic defects in patients with CGD and carriers.

Thirty-four patients with genetically inherited CGD, including 12 patients with X-linked CGD (gp91

deficiency due to cytochrome b-245, beta polypeptide [CYBB] mutations) and 22 patients with autosomal-recessive CGD (p22

, p47

, and p67

deficiency due to cytochrome b-245, alpha polypeptide [CYBA], neutrophil cytosolic factor 1 [NCF1] and NCF2 mutations, respectively) were recruited from different immunology centers and followed up prospectively. Dihydrorhodamine testing and NADPH oxidase subunit expression in white blood cells were determined by flow cytometry.

gp91

and p22

defects, which result in simultaneous loss of both proteins due to their complex formation, were differentiated only by comparative analysis of patients’ and mothers’ intracellular staining. p47

and p67

protein expression was almost undetectable in patients compared with carrier mothers and healthy controls. The expression values of the respective subunits were found to be significantly higher in all controls as compared with carrier mothers, which in turn were higher than those of patients.

Analysis of NADPH oxidase enzyme subunits by flow cytometry in patients and carriers is useful in the rapid prediction of the genetic defect of patients with CGD, thus guiding targeted sequencing and aiding in their early diagnosis.

Analysis of NADPH oxidase enzyme subunits by flow cytometry in patients and carriers is useful in the rapid prediction of the genetic defect of patients with CGD, thus guiding targeted sequencing and aiding in their early diagnosis.The baboons (Papio sp.) exhibit marked interspecies variation in social behavior. The thesis presented here argues, first, that male philopatry is a crucial factor, arguably the crucial factor, underlying the other distinctive features (one-male units, multilevel society) shared by hamadryas and Guinea baboons, but not other species of Papio. The second suggestion is that male philopatry as a population norm was not an adaptation to a particular habitat or set of ecological circumstances but evolved in the common ancestor of hamadryas and Guinea baboons as a response to natural selection in the demographic context peculiar to the frontier of a rapidly expanding population. Other derived features of social structure (male-male tolerance, some facultative female dispersal) subsequently evolved to accommodate male philopatry. The mitochondrial genetic population structure of extant baboons preserves a footprint of the initial expansion of 'modern’ Papio. Immediately after the expansion, male-philopatric, multilevel populations with a general physical and behavioral resemblance to Guinea baboons occupied the whole northern hemisphere range of the genus. Behavioral and physical autapomorphies of hamadryas baboons evolved in a subpopulation of this ancestral northern base, in response to a less productive habitat of the Horn of Africa. Subsequently, ancestral olive baboons 'reinvented’ male dispersal. They and yellow baboons, another male-dispersing species, then replaced most of the male-philopatric northern populations, by male-driven introgression and nuclear swamping.

Tube thoracostomy is a commonly performed procedure in trauma patients. The optimal chest tube size is unknown. This study measures chest tube drainage in a controlled laboratory setting and compares measured flowrates to those predicted by the Hagen-Poiseuille equation.

A model of massive hemothorax was created, consisting of a basin containing synthetic blood substitute (aqueous Glycerin and Xanthan gum) and a standard pleur-evac setup at -20cmH

O suction. Flow measurements were calculated by measuring the time to drain 2L of blood substitute from the basin. Chest tube sizes tested were 20F, 24F, 28F, 32F, and 36F. Thoracostomy opening was modeled using custom built device that represents two ribs, with the distance between varied 2 to 12mm. Flowrate increases were compared against predicted increases according to the Hagen-Poiseuille equation. Percent of predicted increase was calculated, both incremental increase and using 20F tube benchmark.

All tubes were occluded at a 2 mm thoracostomy opening. r flowrates. The 28F is a good balance of reasonable size and high flowrate and is likely the optimal size for most clinical applications.To date, the neurocognitive profile and comorbid psychiatric risks associated with ESES, a syndrome that commonly coincides with a seizure disorder, in contrast to generalized or partial/focal epilepsy without ESES remains unclear. Accordingly, this preliminary study aimed to characterize the neurocognitive differences across pediatric patients with ESES, generalized or focal epilepsy, and risk for comorbid diagnoses (mood disorder, autism, intellectual disability, learning disability, ADHD). We included data from a total of 79 pediatric patients, including those with recently diagnosed ESES (N = 12), generalized epilepsy (GE, N = 25), left focal epilepsy (LFE; N = 20), or right focal epilepsy (RFE; N = 22). All patients completed a neurocognitive evaluation as part of their medical workup and treatment for epilepsy. Cognitive domains assessed include intellectual functioning, verbal/non-verbal reasoning, working memory, processing speed, receptive language, learning and memory. Results showed that children wgreater need for developmentally focused investigations.Presented paper describes the dumped conventional munition catalog that provides up-to-date information about potential hazardous objects lied on the seafloor. Specific aspects of particular types of marine historical ordnance were identified and analyzed, along with a way to catalog objects for their further presentation and development of the program (software). The article discusses the contemporary state of underwater objects from both conflicts using an example of ammunition extracted from Polish maritime areas (Gulf of Gdańsk mainly since the specific role of this basin during World War II). Impact on the maritime environment in terms of human activities together with ecological aspects were outlined. The effects of research and experience on the activities of naval forces and NATO task groups carrying out cyclical actions to destroy underwater objects in the Baltic Sea waters were presented. The role of emerging autonomous technologies for the neutralization of dangerous underwater objects was emphasized as an element that increases the efficiency of such activities.

This study aims to understand how spatial structures, the interconnections between counties, matter in understanding the coronavirus disease 2019 (COVID-19) period prevalence across the United States.

We assemble a county-level data set that contains COVID-19-confirmed cases through June 28, 2020, and various sociodemographic measures from multiple sources. In addition to an aspatial regression model, we conduct spatial lag, spatial error, and spatial autoregressive combined models to systematically examine the role of spatial structure in shaping geographical disparities in the COVID-19 period prevalence.

The aspatial ordinary least squares regression model tends to overestimate the COVID-19 period prevalence among counties with low observed rates, but this issue can be effectively addressed by spatial modeling. Spatial models can better estimate the period prevalence for counties, especially along the Atlantic coasts and through the Black Belt. Overall, the model fit among counties along both coasts is generally good with little variability evident, but in the Plain states, the model fit is conspicuous in its heterogeneity across counties.

Spatial models can help partially explain the geographic disparities in the COVID-19 period prevalence. These models reveal spatial variability in the model fit including identifying regions of the country where the fit is heterogeneous and worth closer attention in the immediate short term.

Spatial models can help partially explain the geographic disparities in the COVID-19 period prevalence. These models reveal spatial variability in the model fit including identifying regions of the country where the fit is heterogeneous and worth closer attention in the immediate short term.

Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammat and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer’s disease.

Solanum lycocarpum St. Hil. (Solanaceae) is widely distributed in the Brazilian Cerrado and is used in folk medicine for treatment of inflammatory disorders, such as asthma and hepatitis, as weel as antirheumatic.

The aims of this study were to evaluate the antioxidant, anti-inflammatory and antinociceptive activities of the ethanol extract (EE) obtained from the ripe fruits of S. lycocarpum and to identify its chemical constituents.

The extract was obtained by percolation with ethanol. This extract was analyzed by liquid chromatography coupled to a diode array detector and mass spectrometer (LC-DAD-MS) for identify its chemical constituents. The antioxidant activity was determined by the reaction with 1,1-diphenyl-2-picrylhydrazyl radical (DPPH). In vivo anti-inflammatory potential was assessed using carrageenan-induced paw edema model, while qualitative and quantitative histological analyses evaluated of the inflammatory infiltrate at different times and treatments. The antinociceptive effect of the Eed the antinociceptive activity of morphine in the both phases the test, but it did not reverse the antinociceptive activity of the EE. The EE (300mg/kg) also caused an increase in the latency to response in the hot-plate test.

The ripe fruits of S. lycocarpum exhibit antioxidant, anti-inflammatory, and antinociceptive activities, attributed mainly to the presence of alkaloids, such as solasodine and peiminine, as well as caffeoylquinic acids in their chemical composition. These results contribute to use of S. lycocarpum ripe fruits for the treatment of inflammatory and painful process.

The ripe fruits of S. lycocarpum exhibit antioxidant, anti-inflammatory, and antinociceptive activities, attributed mainly to the presence of alkaloids, such as solasodine and peiminine, as well as caffeoylquinic acids in their chemical composition. These results contribute to use of S. lycocarpum ripe fruits for the treatment of inflammatory and painful process.

Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes mellitus, contributing to pancreatic dysfunction and insulin resistance. Ameliorating ER stress may be a viable therapeutic approach in the proper management of diabetes mellitus. Cymbopogon citratus (C.citratus) has been used in traditional medicine in the management of diabetes mellitus. Although well known for its anti-diabetic effect, the mechanism underlying this effect remains unclear.

This study was designed to investigate the effect of C. citratus methanolic leaves extract on ER stress induced by streptozotocin (STZ) in wistar rats.

STZ (60mg/kg) was used to induce ER stress in the pancreas of rats. The rats were administered C. citratus methanolic leaves extract via gastric gavage at doses 100, 200 and 400mg/kg for two weeks while metformin (100mg/kg) was used as positive control. Fasting blood glucose (FBG), expression of ER-stress related genes (GRP78, CHOP, ATF4, TRB3, PERK, IRE1), antioxidant (Nrf2 and AhR) and pro-inflammatory (TNF-α) genes were determined.