Johannsenbernard2329

s compared to SS. In addition, burnout was more likely in the 20-39 year old age group, suggesting that special focus should be paid to this age group.

Participants reported overall job satisfaction, and FS did not impact overall burnout. FS was more likely to indicate improvement in control over workload and experienced reduced work-related stress compared to SS. In addition, burnout was more likely in the 20-39 year old age group, suggesting that special focus should be paid to this age group.Upon the approval of disease-modifying therapies (DMTs) for patients with active secondary progressive phase of multiple sclerosis (SPMS), there became an emerging need to prospectively predict and diagnose patients transitioning from the relapsing-remitting to the secondary progressive phase of MS. Whilst several research articles handle the challenges for diagnosing this stage of the disease, a clear step-by-step diagnostic approach remains elusive. This review aims at providing a step-by-step diagnostic approach to patients within 'transitioning' MS based on the currently available research findings and to summarize the gaps in the diagnostic approach and the recommendations for future research in this area of practice.Adversarial examples are usually generated by adding adversarial perturbations on clean samples, designed to deceive the model to make wrong classifications. Adversarial robustness refers to the ability of a model to resist adversarial attacks. And currently, a mainstream method to enhance adversarial robustness is the Projected Gradient Descent (PGD). However, PGD is often criticized for being time-consuming during constructing adversarial examples. Fast adversarial training can improve the adversarial robustness in shorter time, but it only can train for a limited number of epochs, leading to sub-optimal performance. This paper demonstrates that the multi-exit network can reduce the impact of adversarial perturbations by outputting easily identified samples at early exits. Therefore, we can improve the adversarial robustness. Further, we find that the multi-exit network can prevent catastrophic overfitting existing in single-step adversarial training. Specifically, we find that, in the multi-exit network, (1) the norm of weights at a fully connected layer in a non-overfitted exit is much smaller than that in an overfitted exit; and (2) catastrophic overfitting occurs when the late exits have weight norms larger than the early exits. Based on these findings, we propose an approach to alleviating the catastrophic overfitting of the multi-exit network. Compared to PGD adversarial training, our approach can train a model with decreased time complexity and increased empirical robustness. Extensive experiments have been conducted to evaluate our approach against various adversarial attacks, and the experimental results demonstrate superior robustness accuracies on CIFAR-10, CIFAR-100 and SVHN.The objective of the present study was the development and validation of the method for determining AMB-FUBINACA and its metabolite - AMB-FUBINACA O-desmethyl acid - in blood samples, followed by verification of the method in toxicological judicial and forensic medicine practice employing the example of post-aggression suicide. Most likely in consequence of development of adverse effects resulting in psychotic symptoms, a male being under the influence of the synthetic cannabinoid AMB-FUBINACA and the new synthetic opioid U-47700, mortally wounded his female partner and subsequently committed suicide. Identification and determination of the afore-mentioned xenobiotics in blood samples collected from the male and female victims were performed employing high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The analytes were isolated from blood samples using the solid phase extraction (SPE) method. The blood samples collected from the male and female demonstrated respectively 110 and 196 ng/mL of AMB-FUBINACA O-desmethyl acid metabolite, 1935 and 357 ng/mL of U-47700, 250 and 200 ng/mL of N-desmethyl-U-47700, as well as 410 and 200 ng/mL of N,N-didesmethyl-U-47700. The concentration values of new psychoactive substances (NPS's) in blood samples originating from the male and female were within the ranges encountered in cases of poisoning, including these resulting in death. Nevertheless, the evident signs of exsanguination proof that the woman was alive when she sustained lethal injuries. The presented cases illustrate the difficult to be anticipated effect exerted on the users by NPS's.Family caregivers play an increasingly important role in providing care services, especially for the aging population. Currently, evidence on compassion fatigue among family caregivers remains limited. Our study aims to assess the levels and related factors of compassion fatigue and compassion satisfaction in family caregivers. We searched nine electronic databases for published observational studies up to 7 October 2021. In our studies, the pooled mean scores of compassion fatigue and compassion satisfaction were 42.35 (95% CI 28.45-56.24) and 36.41 (95% CI 33.63-39.19), respectively. We considered background, role-related, and social psychological variables to influence the risk of compassion fatigue and compassion satisfaction. Current data suggest that overall compassion fatigue and compassion satisfaction levels were moderate, thus highlighting the potential risk of compassion fatigue for family caregivers. In the future, these findings can be used to develop programs that will mitigate compassion fatigue and improve compassion satisfaction in family caregivers.Exposure to adverse childhood experiences (ACEs) is a risk factor for adolescent cannabis use (CU). We explored whether family communication and school connectedness can offer direct protection (the compensatory model of resiliency) or moderating protection (the protective factors model of resiliency). Using cluster random sampling, a Youth Risk Behavior Survey (YRBS) was conducted with 5,341 middle school and 4,980 high school students in 2019. Generalized estimating equations were used to estimate whether family communication and school connectedness offered independent direct protection (multiple regression) or moderating protection (multiplicative interaction) in the relationship between ACEs and past 30-day CU. Adjusted prevalence ratios (APR) and 95% confidence intervals (95% CI) were calculated. There was a graded relationship between ACEs and past 30-day CU for all students that was particularly strong among middle school students 1 ACE (APR = 2.37, 95% CI = 2.16, 2.62), 2 ACEs (APR = 2.89, 95% CI = 2.60, 3.23), 3 ACEs (APR = 5.30, 95% CI = 4.75, 5.90), 4 + ACEs (APR = 7.86, 95% CI = 7.13, 8.67). Results supported the compensatory model of resiliency with both family communication (middle school APR = 0.90, 95% CI = 0.88, 0.93; high school APR = 0.90, 95% CI = 0.87, 0.93) and school connectedness (middle school APR = 0.76, 95% CI = 0.72, 0.79; high school APR = 0.72, 95% CI = 0.68, 0.77) demonstrating a direct, independent protective relationship with past 30-day CU. There was no consistent evidence supporting the protective factors resiliency model.

Impact of pre-interventional magnetic resonance angiography (MRA) on prostatic artery embolization (PAE) regarding workflow, radiation dose, and clinical outcome.

Retrospective evaluation of 259 patients (mean age 68±9, range 41-92) with benign prostatic hypertrophy (BPH) undergoing PAE between January 2017 and December 2020. MRA was performed in 137 cases. In 122 patients, no pre-interventional MRA was performed. Origin of the PA, volumetry of the prostatic gland and ADC values were evaluated. International Prostate Symptom Score (IPSS), Quality of Life (QoL) and International Index of Erectile Function (IIEF) were evaluated before and after PAE.

Origin of the PA was identified in all cases. Significant differences regarding volume reduction (-20±13ml with MRA vs -17±9ml without MRA) and ADC value reduction were found (-78±111 10

mm

/s with MRA vs -45±99 10

mm

/s without MRA). PAE workflow was modified in 16 patients due to MRA findings. Radiation dose (5518.54±6677.97 µGym

with MRA vs 23963.50±19792.25 µGym

without MRA) and fluoroscopy times (19.35±9.01min. with MRA vs 27.45±12.54min. without MRA) significantly differed. IPSS reduction improved (-11±8 points with MRA vs -7±9 points without MRA, p<0.001), while QOL (-2±1 points with MRA and -2±2 points without MRA) and IIEF (+2±10 points with MRA and +1±11 points without MRA) showed no significant differences (p>0.05).

Pre-interventional MRA facilitates improved workflow and patient safety of PAE while reducing radiation dose and intervention time.

Pre-interventional MRA facilitates improved workflow and patient safety of PAE while reducing radiation dose and intervention time.Numerous preclinical and clinical studies have demonstrated the significant contribution of inflammation to the development and progression of various types of cancer. Inflammation in the tumor microenvironment mediates complex interactions between innate immunity, adaptive immunity, microbiomes and stroma, and ultimately alters the overall fitness of tumor cells at multiple stages of carcinogenesis. Malignancies are known to arise in areas of chronic inflammation and inflammation in the tumor microenvironment (often called tumor-promoting inflammation) is believed to allow cancer cells to evade immunosurveillance while promoting genetic instability, survival and progression. Among the strongest data suggesting a causal role for inflammation in cancer come from the recent CANTOS trial which demonstrated that interleukin-1β (IL-1β) inhibition with canakinumab leads to a significant, dose-dependent decrease in incident lung cancer. This observation has launched a series of additional clinical studies to understand the role of IL-1β and the inflammasome in cancer, and the clinical utility of IL-1β inhibition in different stages of lung cancer. In this article we will review recent data implicating IL-1β signaling and its upstream regulator NLRP3 in both solid tumor and hematologic malignancies. We will discuss the key preclinical observations and the current clinical landscape, and describe the pharmacologic tools which will be used to evaluate the effects of blocking tumor-promoting inflammation clinically.

The variation in the immune response to Bartonella spp. infection in humans remains unclear. The present study compares the expression of selected interleukins, cytokines and cathelicidin (LL-37) in rheumatology clinic patients suffering from musculoskeletal symptoms with healthy blood donors. The patients had previously been tested for the presence of Bartonella henselae antibodies.

Gene expression of LL-37, interleukin (IL)-2, IL-4, IL-6, IL-12, interferon-(IFN)-γ, and tumor necrosis factor (TNF-α)-α was determined in blood samples using quantitative Polymerase Chain Reaction (qPCR). Statistical analysis was prepared with STATISTICA.

Statistically significant differences in the mRNA levels of the tested cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-12; p<0.0001) were observed between the healthy controls and patients; however, no difference was observed for LL37 mRNA (p​=​0.1974). No significant differences in mRNA expression were observed between IgG in anti-Bartonella seropositive and seronegative individuals (p>0.05). The only significant differences between the Bartonella spp. DNA positive and negative patients, indicated by PCR, were observed for TNF-α and IL-12 mRNA (p​=​0.0045 and p​=​0.0255, respectively).

A broadly similar immune response to the tested cytokines was observed among the participants irrespective of anti-Bartonella spp. IgG seropositivity. However, the Bartonella DNA-positive participants demonstrated significantly lower expression of IL-12 and TNF-α mRNA; this may indicate that these bacteria have a suppressive influence on the immune system.

A broadly similar immune response to the tested cytokines was observed among the participants irrespective of anti-Bartonella spp. IgG seropositivity. However, the Bartonella DNA-positive participants demonstrated significantly lower expression of IL-12 and TNF-α mRNA; this may indicate that these bacteria have a suppressive influence on the immune system.Conscious perception often fails when an object appears unexpectedly and our attention is focused elsewhere (inattentional blindness). While various factors have been identified that modulate the likelihood of this failure of awareness, the semantic value of facial emotional expression of the unexpected stimulus is not clear. A total of 457 participants performed a static or a dynamic inattentional blindness paradigm with one of three face icons as the unexpected stimulus. Whereas we only found an effect of frowning faceś semantic value on its conscious detection in the static paradigm, we found in both paradigms a substantial effect of frowning as well as happy faceś semantic value on their conscious identification. Thus, we assume that the semantic value of unexpected stimuli, based on facial emotional expressions, controls attentional prioritization and influences inattentional blindness. Furthermore, we argue that every finding in inattentional blindness research should be considered in its respective context.Urban arterials form the main structure of city street networks, and typically have high traffic volume and high crash frequency. To reduce the number of crashes, hotspot identification (HSID) is the first step in the traffic safety management process, and often utilizes crash prediction models. Classical crash prediction models investigate the relationship between roadway characteristics and traffic safety at the micro level, that is, they treat road segments and intersections as isolated units. Micro-level analysis has limitations, however, when examining urban arterial crashes 1) signal spacing is typically short for urban arterials in dense street networks, and there are interactions between intersections and road segments that classical models do not accommodate; and 2) for practical engineering, a hotspot to which countermeasures are applied generally consists of several adjacent intersections and road segments instead of a single intersection or road segment. To address these concerns, signalized interombination of micro- and meso-level hotspots should be recommended to local transportation authorities.Babesia bovis and B. bigemina are tick-transmitted parasites causing bovine babesiosis, characterized by significant morbidity and mortality leading to economic losses to the livestock industry in tropical and subtropical regions worldwide. Animals that recover from acute infection remain carriers with low parasitemia acting as a source of transmission, and often escape detection. An improved diagnosis of a B. bovis and/or B. bigemina infection of carrier animals is enabled by the availability of detection methods with high sensitivity. To this end, two nested PCR assays targeting the cytochrome b (cytb) genes of B. bovis and B. bigemina (cytb-nPCR), have been recently developed and an increased sensitivity with respect to reference protocols has been shown (Romero-Salas et al., 2016). In this study, the specificity against a panel of hemoparasites that potentially co-occur with B. bovis and B. bigemina was demonstrated to ensure applicability of the cytb-nPCR assays in a wide range of regions where bovine baerably higher number of chronically infected B. bovis and B. bigemina carrier animals compared to reference nPCR and qPCR protocols, when applied in different epidemiological field situations. Furthermore, a high reproducibility between laboratories could be demonstrated.

Loganin and morroniside are two iridoid glycosides with anti-inflammatory, antioxidant and anti-tumor effects. Whether they have effect on acute lung injury and pulmonary fibrosis are still unknown.

To explore the potential effects of loganin and morroniside against acute lung cancer and pulmonary fibrosis, and the underlying molecular mechanism.

Cell and animal models of acute lung injury were established by the induction of LPS. After intervention with loganin and morroniside, the pathological symptom of lung tissue was assessed, pro-inflammatory factors in cells and lung tissues were detected, NF- κB/STAT3 signaling pathway related proteins were detected by western blotting. Mice pulmonary fibrosis model was induced by bleomycin, pathological symptom was assessed by HE and Masson staining. Fibrosis related indicators were detected by qPCR or western blot. CD4+/CD8+ was detected by flow cytometry.

Loganin and morroniside relieved the pathological symptom of lung tissue in acute lung injury, pro-infland pulmonary fibrosis, and may provide theoretical basis for the development of new clinical drugs.

The genus Callistemon belongs to a group of medically significant plants which have found tremendous use in traditional medicine across the globe. They are reported for anti-cancer, neuroprotective, anti-inflammatory, antioxidant, anti-microbial, and many other significant medicinal attributes. However, the current use of this genus is limited mainly to ornamental and recreational purposes. Recent studies have reported several novel compounds like phloroglucinol derivatives, terpenes, phenolics, etc., from Callistemon spp., which have great medical significance. Further, there is a surge of recent studies reporting novel pharmacological properties of Callistemon. The number of review studies discussing the underlying molecular mechanism behind the pharmacological action of Callistemon is quite limited.

The literature search for studies published from 1991 to 2021 using Google scholar and PubMed were selected. The review documented relevant literature focused on Callistemon spp exhibiting significant pharmacological effects.

This review deals with the pharmacological properties of Callistemon and the underlying molecular mechanism responsible for protective effect in several pathophysiological conditions. This study updated the current information regarding the medicinal importance of Callistemon spp. for research and the public community.

The preliminary studies, interrogating pharmacological properties of Callistemon spp., hold great promise and demand further research to decipher the mode of action. More and more research are needed in this direction to explore the full potential of the genus Callistemon as a medicinal herb.

The preliminary studies, interrogating pharmacological properties of Callistemon spp., hold great promise and demand further research to decipher the mode of action. More and more research are needed in this direction to explore the full potential of the genus Callistemon as a medicinal herb.

Cerebral ischaemia-reperfusion injury (CIRI) is a common disease characterized by severe attacks and a high disabling rate worldwide. Oxidative stress injury has been proposed as a major risk factor for CIRI. Ginkgo biloba extract (GBE) has been shown to elicit vascular protective effects, the main components of which are Ginkgo flavonoids (GF) and ginkgolides (GL). Our previous study showed that GF and GL played a central role in protecting CIRI, but the mechanism remains unclear. This study aimed to further reveal the protective effect mechanism of GF and GL in rats with CIRI.

The antioxidant activity in vitro was assessed by the DPPH method. The model used in this study was established by middle cerebral artery occlusion (MCAO) and reperfusion; the level of CIRI was assessed by nerve function score and TTC staining; we measured the oxidative stress indices in the brain cortex, including LDH, GSH-Px, and the protein contents of Akt, p-Akt, Nrf2, and HO-1; HPLC-MS was used to detect drug concentrations iRI by activating the PI3K/Akt/Nrf2 signalling pathway and promoting multicomponent interactions in vivo.

After GF and GL were used in combination, the effect of anti-CIRI was more pronounced. This result indicated that GF and GL might improve CIRI by activating the PI3K/Akt/Nrf2 signalling pathway and promoting multicomponent interactions in vivo.

Samhwangsasim-tang (SST) is a traditional medicine used to treat hypertension and arteriosclerosis. Additionally, due to the effects of its constituent herbs, SST is considered effective for memory-related disorders.

We investigated the effects of SST on neuronal survival and memory in glutamate-induced hippocampal cells and in a mouse model of scopolamine-induced memory impairment.

SST components were identified using 3D-ultra performance liquid chromatography (3D-UPLC). In vitro, we induced glutamate-induced excitotoxicity in HT22 cells after SST pretreatment. We used a cell counting kit-8 and cell cytotoxicity assay, flow cytometry, and western blotting to test the protective effects of SST on neuronal death. In vivo, C57BL/6J mice were administered with 150 and 300 mg/kg SST once daily for 7 days and then intraperitoneally injected with 1 mg/kg scopolamine for 7 days to induce cognitive impairment. We then measured cognitive behavior using a novel object recognition test (NORT) and passive avoidancehe scopolamine-treated mouse hippocampus.

Our results suggest that SST has neuroprotective effects to attenuate neuronal cell death and oxidative stress through CREB/JNK signaling via BDNF activation. SST may regulate endogenous survival factors in the hippocampus, which may be a safe and potential clinical treatment for cognitive impairment in AD.

Our results suggest that SST has neuroprotective effects to attenuate neuronal cell death and oxidative stress through CREB/JNK signaling via BDNF activation. SST may regulate endogenous survival factors in the hippocampus, which may be a safe and potential clinical treatment for cognitive impairment in AD.The receptor tyrosine kinase (RTK) anexelekto (AXL) is mutated and/or overexpressed in various malignancies, and plays a central role in tumor development and acquired drug resistance. Although highly selective inhibitors have been developed in recent years, direct inhibition of AXL may block its ubiquitination, eventually leading to surface accumulation of the protein. Herein, we designed and synthesized a series of AXL degraders with high selectivity and without compensatory increase of AXL. In particular, compounds 20 and 22 showed significant AXL degradation capacity, which inhibited the proliferation and migration of cancer cells in vitro. In addition, these compounds induced the formation of cytoplasmic vacuoles and triggered methuosis, a new type of non-apoptotic cell death, by stimulating excessive production of macropinosomes. Vacuole formation was mediated via H-Ras activation, and was attenuated upon inhibition of its downstream regulatory factor Rac1. Furthermore, compound 20 inhibited the growth of tumor cell xenografts in vivo, and prolonged the survival of the tumor-bearing mice.Thirty-two clofazimine derivatives, of which twenty-two were new, were synthesized and evaluated for their antiviral effects against both rabies virus and pseudo-typed SARS-CoV-2, taking clofazimine (1) as the lead. Among them, compound 15f bearing 4-methoxy-2-pyridyl at the N5-position showed superior or comparable antiviral activities to lead 1, with the EC50 values of 1.45 μM and 14.6 μM and the SI values of 223 and 6.1, respectively. Compound 15f inhibited rabies and SARS-CoV-2 by targeting G or S protein to block membrane fusion, as well as binding to L protein or nsp13 to inhibit intracellular biosynthesis respectively, and thus synergistically exerted a broad-spectrum antiviral effect. The results provided useful scientific data for the development of clofazimine derivatives into a new class of broad-spectrum antiviral candidates.The pentasaccharide fondaparinux is a synthetic anticoagulant based on heparin antithrombin-binding sequence. Fondaparinux improves safety and predictable pharmacodynamics compared with heparins; however, it requires a complicate synthesis process which contain more than 50 steps of synthesis. Herein, we designed and synthesized four fondaparinux analogues (compounds 1, 2, 3, 4) using a [2+3] convergent synthetic method, which greatly simplified the synthetic process, improved the product yield, and curtailed the expenditures. These synthesized compounds showed stronger anticoagulant activities by factor Xa inhibition (IC50 725-1126 nM vs. 1909 nM for fondaparinux) in the AT-dependent manner. After subcutaneous (s.c.) administration to rats, the compounds displayed long-lasting anti-factor Xa activities and inhibition of thrombin generation ex vivo. Compared with fondaparinux, these compounds were slowly eliminated after s.c. administration to rats, the half-lies (t1/2) were more than 2-fold of that of fondaparinux. These results suggested the pentasaccharide analogues may exhibit better pharmacokinetic and predictable pharmacodynamic characteristics.A set of structurally related diphenylurea derivatives bearing aminoguanidine moiety were synthesized, and their antibacterial activity was assessed against a panel of multi-drug resistant Gram-positive clinical isolates. Two compounds 6 and 24 were identified with better bacteriological profile than the lead compound I. The multi-step resistance development studies indicated that MRSA are less likely to develop resistance toward diphenylurea compounds. Moreover, these compounds demonstrated a prolonged post-antibiotic effect than that of vancomycin. Furthermore, compounds 6 and 24 were able to re-sensitize VRSA to vancomycin, resulting in 8- to more than 32-fold improvement in vancomycin MIC values against clinical VRSA isolates. Finally, when assessed in an in vivo skin infection mouse model, the efficacy of compound 24 was very comparable to that of the commercially available fusidic acid ointment. Additionally, the diphenylurea 24 did not have a pronounced effect on the animal weights along the experiment indicating its safety and tolerability to mice. Taken together, these results indicate that the diphenylurea scaffold merits further investigation as a promising anti-staphylococcal treatment option.Ferrociphenols are characterized by the presence of a biologically active redox motif [ferrocenyl-ene-p-phenol], and are known to exhibit anticancer properties. Recent studies have identified a new series of ferrociphenols that bear an imido-type heterocycle at the terminus of a short alkyl chain, and which showed very strong antiproliferativity against multiple types of cancer cells. This work describes the syntheses and an SAR study of ferrociphenols bearing a diversity-based range of nitrogen-containing substituents on the alkyl chain. Preliminary oxidative metabolism experiments and ROS-related bioactivity measurements were also carried out to probe the origin of the cytotoxicity of the imido-ferrociphenols. Furthermore, an interesting dimerization phenomenon was observed in the X-ray crystal structure of the 2,3-naphthalenedicarboximidopropyl-ferrocidiphenol, 21, which may be a factor in decreasing its rate of oxidation to form the corresponding quinone methide, 21-QM, thereby affecting its antitumor activity. These results suggest that both the formation rate and the stability of QMs could affect the antiproliferative activity of their ferrociphenol precursors.Pimavanserin is a selective 5-HT2A receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson's disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7-1∼7-37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7-16 exhibited 50-fold higher 5-HT2A receptor antagonist activity (IC50 = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC50 = 2.1 vs 50 nM) than pimavanserin. Moreover, 7-16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7-16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7-16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy complication. However, the pathogenesis of ICP is currently unclear.

We analyzed the placenta samples of 10 normal and 10 ICP pregnant women. the expressions of circ0060731, miR-21-5p, and their downstream target genes PDCD4, ESR1, and apoptotic protein cleaved-caspase3 were detected in the cell model.

The expression of Circ_0060731, PDCD4, ESR1, and caspase-3 was higher in the ICP placenta tissue than in the control group, and the expression of miR-21-5p was lower in the ICP group than in the control group. In HTR8/Svneo cells treated with TCA, the expression/levels of Circ_0060731, PDCD4, ESR1, and caspase-3 were significantly higher in the ICP group than in the control group, and miR-21-5p was significantly lower in the ICP group than in the control group. Lentiviral knockdown of miR-21-5p significantly increased the expressions of its downstream genes of PDCD4 and ESR1, and also increased cell apoptosis. Overexpression of miR-21-5p significantly reduced the expression of PDCD4 and ESR1 and reduced cell apoptosis. The dual-luciferase experiment showed that both PDCD4 and ERS1 were the target genes of miR-21-5p.

Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway could induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.

Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway could induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.

Mandibular condyle chondrocytes (MCCs) are exposed to various mechanical environments. Primary cilia, as a carrier for ion channels, can sense mechanical signals. Intraflagellar transport protein 88 (IFT88) is crucial for the assembly and function of primary cilia. Piezo1 is a mechanically activated ion channel that mediates mechanical signal transduction. This study aimed to identify the possible synergistic effect between Piezo1 and IFT88 in MCC differentiation during mechanical conduction.

Confocal immunofluorescence staining was used to reveal the Piezo1 localization. Small interfering RNA (siRNA) technology was used to knock down the expression levels of Piezo1 and IFT88. The chondrogenic differentiation ability of MCCs was evaluated by Alcian blue staining, and the early differentiation ability was evaluated by Western blot of SOX9 and COL2A1.

Confocal immunofluorescence results showed that Piezo1 localized in the root of primary cilia. Without cyclic tensile strain (CTS) stimuli, Alcian blue staining showed that Piezo1 knockdown had a marginal effect on the chondrogenic differentiation of MCCs, while IFT88 knockdown inhibited the chondrogenic differentiation. The protein levels of SOX9 and COL2A1 decreased significantly with CTS stimuli. However, these protein levels were restored when Piezo1 was knocked down. In addition, IFT88 knockdown decreased the protein level of Piezo1 with or without CTS.

Piezo1 and IFT88 might play a synergistic role in regulating MCC differentiation under CTS stimuli.

Piezo1 and IFT88 might play a synergistic role in regulating MCC differentiation under CTS stimuli.

For neurological simulation, an accurate deformation model of brain tissue is of key importance for faithful visual feedback. Existing models, however, do not take into account intracranial pulsation, which degrades significantly the realism of visual feedback.

In this paper, a finite element model incorporating intracranial pressure is proposed for simulating brain tissue deformation with pulsation. An implicit Euler method is developed to calculate the deformation of brain tissue. A circuit model of intracranial pressure dynamics is established based on cerebral blood and cerebrospinal fluid circulations. The intracranial pulsation of pressure is introduced into the deformation model, so that the simulated brain tissues pulsate with a rhythm in accord with the changes of intracranial pressure, which resembles real-life neurosurgery.

The experimental implementation of the proposed deformation model and the calculation method shows that it provides realistic simulation of brain tissue pulsation and real-time performance is achieved on an ordinary computer for certain procedures of neurosurgery.

The experimental implementation of the proposed deformation model and the calculation method shows that it provides realistic simulation of brain tissue pulsation and real-time performance is achieved on an ordinary computer for certain procedures of neurosurgery.

Interactive surgical simulation using the finite element method to model human skin mechanics has been an elusive goal. Mass-spring networks, while fast, do not provide the required accuracy.

This paper presents an interactive, cognitive, facial flaps simulator based on a projective dynamics computational framework. Projective dynamics is able to generate rapid, stable results following changes to the facial soft tissues created by the surgeon, even in the face of sudden increases in skin resistance as its stretch limit is reached or collision between tissues occurs. Our prior work with the finite element method had been hampered by these considerations. Surgical tools are provided for; skin incision, undermining, deep tissue cutting, and excision. A spring-like "skin hook" is used for retraction. Spring-based sutures can be placed individually or automatically placed as a row between cardinal sutures.

Examples of an Abbe/Estlander lip reconstruction, a paramedian forehead flap to the nose, a retroauricular flap reconstruction of the external ear, and a cervico-facial flap reconstruction of a cheek defect are presented.

Projective dynamics has significant advantages over mass-spring and finite element methods as the physics backbone for interactive soft tissue surgical simulation.

Projective dynamics has significant advantages over mass-spring and finite element methods as the physics backbone for interactive soft tissue surgical simulation.

Retinal image segmentation can help clinicians detect pathological disorders by studying changes in retinal blood vessels. This early detection can help prevent blindness and many other vision impairments. So far, several supervised and unsupervised methods have been proposed for the task of automatic blood vessel segmentation. However, the sensitivity and the robustness of these methods can be improved by correctly classifying more vessel pixels.

We proposed an automatic, retinal blood vessel segmentation method based on the U-net architecture. This end-to-end framework utilizes preprocessing and a data augmentation pipeline for training. The architecture utilizes multiscale input and multioutput modules with improved skip connections and the correct use of dilated convolutions for effective feature extraction. In multiscale input, the input image is scaled down and concatenated with the output of convolutional blocks at different points in the encoder path to ensure the feature transfer of the original t of the original U-net and other U-net-based architectures, as well as many other state-of-the-art segmentation techniques, and that the proposed method is robust to noise.Foods prepared from the Asteraceae family are known to exert in vitro antioxidant activity. For example, roots and fruit extracts from dandelion were found to possess antioxidant and anti-platelet potential in two in vitro models (washed blood platelets and whole blood). However, little is known of other extracts from the Asteraceae, such as chicory leaves, green lettuce leaves, red lettuce leaves, and Jerusalem artichoke roots, on the hemostatic system. Of all the tested extracts from the Asteraceae, dandelion root extract and dandelion fruit extracts appear to have the strongest anti-platelet potential in whole blood, while red lettuce leaves and Jerusalem artichoke roots demonstrated the strongest anti-platelet activity in washed blood platelets. Our results suggest that the members of the Asteraceae family, especially red lettuce leaves and Jerusalem artichoke roots, possess compounds that may exert beneficial anti-platelet effects. However, although Asteraceae plant organ extracts were found to demonstrate activity in vitro, further in vivo studies are needed to determine their true effects on cardiovascular disease.

Chronic inflammatory diseases are major causes of global morbidity and mortality. Acute inflammation is meant to protect the body against foreign agents, but it also plays a major role in tissue repairment. Several mediators are involved in this process, including pro-inflammatory cytokines produced by macrophages. Occasionally, if the inflammatory response is not resolved, the acute inflammatory process can evolve into a chronic inflammation. Natural compounds from vegetables are considered as an important source of active agents with potential to treat or prevent inflammatory related pathologies and could be used as an alternative of the therapeutic agents currently in use, such as non-steroidal anti-inflammatory drugs (NSAIDs), which present several side effects.

In this research work we evaluated in vitro the anti-inflammatory activity of a series of ten phytochemicals present in Brassica, measured as the potential of those compounds to reduce the production of key pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) by a human macrophage-like cell model of HL-60 cells RESULTS Most of the tested phytochemicals (including the most representative bioactive molecules of the major classes of compounds present in cruciferous foods such as glucosinolates, isothiocyanates, hydroxycinnamic acids, flavonols and anthocyanins) demonstrated significant anti-inflammatory activity at micromolar level in the absence of cytotoxic effects in this human macrophage-like cell model.

These data confirm that phytochemicals commonly obtained from Brassica may be potential therapeutic leads to treat or prevent human chronic inflammation and related diseases.

These data confirm that phytochemicals commonly obtained from Brassica may be potential therapeutic leads to treat or prevent human chronic inflammation and related diseases.Adrenocortical carcinoma (ACC) is one of the deadliest endocrine malignancies and telomere maintenance by activated telomerase is critically required for ACC development and progression. Because telomerase reverse transcriptase (TERT) and regulator of telomere elongation helicase 1 (RTEL1) play key roles in telomere homeostasis, we determined their effect on ACC pathogenesis and outcomes. Analyses of TCGA and GEO datasets showed significantly higher expression of RTEL1 but not TERT in ACC tumors, compared to their benign or normal counterparts. Furthermore, gains/amplifications of both TERT and RTEL1 genes were widespread in ACC tumors and their expression correlated with their gene copy numbers. Higher expression of either TERT or RTEL1 was associated with shorter overall and progression-free survival (OS and PFS) in the TCGA ACC patient cohort, and higher levels of both TERT and RTEL1 mRNA predicted the shortest patient OS and PFS. However, multivariate analyses showed that only RTEL1 independently predicted patient OS and PFS. Gene set enrichment analysis further showed enrichments of wnt/β-catenin, MYC, glycolysis, MTOR, and DNA repair signaling pathways in ACC tumors expressing high TERT and RTEL1 mRNA levels. Taken together, TERT and RTEL1 promote ACC aggressiveness synergistically and may serve as prognostic factors and therapeutic targets for ACC.Although pain has lower mortality rates than cancer, diabetes and stroke, pain is a predominate source of distress and disability. However, the management of pain remains an enormous problem. Many drugs used to pain treatment have more or less side effects. Therefore, the development of novel therapeutic target is critical for the treatment of pain. Notably, studies have shown that adipocytokines have a dual role in pain. Growing shreds of evidence shows that the levels of adipocytokines are upregulated or downregulated in the development of pain. In addition, substantial evidence indicates that regulation of adipocytokines levels in models of pain attenuates or promotes pain behaviors. In this review, we summarized and discussed the effect of adipocytokines in pain. These evidence indicates that adipocytokines attenuate or promote pain behaviors through interacting with their receptors, activating serotonin pathway, interacting with μ-opioid receptor, activating microglia, infiltrating macrophage and so on. Overall, adipocytokines have some potential in treating pain, but the underlying mechanisms remain unclear and need to be further studied.Intracerebral hemorrhage (ICH) has a high mortality and disability rate. Fewer studies focus on white matter injury (WMI) after ICH, especially the corticospinal tract (CST) injury located in the spinal cord, which correlates with motor impairments. Recent studies have shown that gut microbiota dysbiosis occurs after ICH. Furthermore, NLRP3 inflammasome can be activated after ICH, resulting in inflammatory cascade reactions and aggravating brain injury. However, no direct and causal correlation among NLRP3 inflammasome inhibition, altered gut microbiota, and CST injury following ICH has been reported. This study aimed to investigate the effect of MCC950, a selective NLRP3 inflammasome inhibitor, on the gut microbiota and CST injury after ICH. We observed that compared with the sham group, the members of Firmicutes, such as Faecalibaculum and Dubosiella, were depleted in the ICH + Vehicle group, whereas the members of Proteobacteria and Campilobacterota were enriched, such as Enterobacter and Helicobacter. After treatment with MCC950, the Bacteroides, Bifidobacterium and Paenibacillus were relatively abundant in the gut flora of mice. Moreover, we observed CST injury located in cervical enlargement of the spinal cord, and MCC950 alleviated it. Furthermore, treatment with MCC950 decreased the mNSS score and brain water content in ICH. Taken together, the present study showed that MCC950 modulated gut microbiota, effectively attenuated CST injury located in cervical enlargement of the spinal cord, and ameliorated neurological deficits after ICH. This study provided a novel report that links NLRP3 inflammasome inhibition, gut microbiota alteration and CST injury following ICH and profound implications for ICH treatment.

The clinical phenotypes of frontotemporal dementia (FTD) are defined by distinctive clinical features and associated with unique cortical atrophy patterns. Clinical manifestations in FTD however are not solely driven by cortical pathology, but stem from the selective dysfunction of corticobasal circuits, the majority of which are relayed through thalamic nuclei. The objective of this study is the systematic radiological characterisation of thalamic pathology across the clinical spectrum of FTD to describe phenotype-associated thalamic signatures.

170 participants were included in a multimodal, prospective neuroimaging study to evaluate thalamic degeneration at a nuclear, vertex, and morphometric level using a uniform imaging protocol and a multimodal analysis approach.

Patients with behavioural variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA) and amyotrophic lateral sclerosis-FTD (ALS-FTD) exhibit distinctive thalamic diseical change and differ in their sensitivity to detect distinguishing features, future studies should implement a multimodal approach with complementary MRI techniques.

Arterial spin labeling (ASL) and diffusion-weighted imaging (DWI) are useful for assessing hyperperfusion and cytotoxic edema, respectively, caused by acute seizures. This study investigated the clinical characteristics associated with normal ASL findings and DWI abnormalities in patients with acute seizures.

Overall, 41 patients with ASL and DWI images that were obtained within 48h of focal onset seizure diagnosis, due to epilepsy or acute symptomatic seizures, were divided into groups based on initial ASL findings (ASL-negative vs. ASL-positive), and DWI abnormalities (DWI-negative vs. DWI-positive). The diagnosis was made based on seizure semiology, electroencephalography, and conventional imaging modalities. ASL and DWI abnormalities were based on visual assessment.

Of the 41 patients, eight (19.5%) displayed normal ASL findings. The proportion of patients with focal aware seizures (FAS) was significantly higher among ASL-negative patients (62.5%) than that in ASL-positive patients (15.2%); the proportion of patients with focal impaired awareness seizures (FIAS) was significantly lower among ASL-negative patients (12.5%) than that among ASL-positive patients (57.6%). Hyperintensity findings on DWI were observed in 12 patients (29.3%, DWI-positive). The proportion of patients with FIAS was significantly higher among DWI-positive patients (75.0%) than that among DWI-negative patients (37.9%). Multivariate analysis revealed that FAS and FIAS were associated with normal ASL findings (odds ratio [OR] 21.37, P=0.010) and DWI abnormalities (OR=6.11, P=0.028).

A diagnosis of seizures should not be excluded based on normal ASL findings, especially in patients with FAS. FIAS may be a risk factor for neuronal damage caused by seizure activity.

A diagnosis of seizures should not be excluded based on normal ASL findings, especially in patients with FAS. FIAS may be a risk factor for neuronal damage caused by seizure activity.Telangiectasia, hereditary hemorrhagic, type 2 (HHT2) is a rare autosomal dominant disease caused by a mutated ACVRL1 gene (Letteboer et al., 2005). The peripheral blood mononuclear cells (PBMCs) from a patient carrying a heterozygous 2 bp duplication in intron 6 of the ACVRL1 gene, NG_009549.1(NM_000020.2)c.772 + 3_772 + 4dup, were reprogrammed using episomal vectors. The inserted mutation in ACVRL1 will causes the abnormal splicing, which will be associated with HHT2. The cell line will enable proper in vitro disease modelling of HHT2(Roman and Hinck, 2017).We report the generation of four human iPSC lines (8993-A12, 8993-B12, 8993-C11, and 8993-D7) from fibroblasts of four patients affected by maternally inherited Leigh syndrome (MILS) carrying homoplasmic mutations m.8993T > G or m.8993T > C in the mitochondrial gene MT-ATP6. We used Sendai viruses to deliver reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The established iPSC lines expressed pluripotency markers, exhibited a normal karyotype, were capable to form cells of the three germ layers in vitro, and retained the MT-ATP6 mutations at the same homoplasmic level of the parental fibroblasts.

To describe and examine the theories, components, and effectiveness of self-management support interventions for individuals experiencing cancer-related fatigue.

A systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 Statement. CINAHL, PubMed, Cochrane CENTRAL, and EMBASE were searched (from inception to June 2021) for randomised controlled trials examining self-management support interventions for managing cancer-related fatigue. Data were screened, extracted, and appraised by two authors. Data extraction was guided by the Self-management Support Taxonomy (i.e., a modified version of the Practical Reviews in Self-Management Support Taxonomy tailored to cancer). The Revised Cochrane Risk of Bias tool was used for study appraisal. A critical narrative synthesis was conducted.

Fifty-one papers representing 50 different studies (n=7383) were identified. Most interventions were delivered post-treatment (40%) using in-person (i.e., 'facort strategies and the application of a behavioral theory influence behavior change. Program developers should guide self-management support with a behavioral theory, and describe their theory application in intervention development, implementation, and evaluation; ensure facilitators receive adequate support training; and seek the delivery preferences of cancer survivors. Future research should incorporate adequate follow-up to sufficiently evaluate the impact of programs on cancer-related fatigue and associated self-management behaviors. Findings from this review are relevant to all healthcare professionals, but are of most relevance to nurses as the largest cancer care workforce with a key role in delivering self-management support.The FMR1 premutation has been associated with difficulties in executive functioning, including verbal inhibition. However, little is known about the longitudinal profiles of verbal inhibition among FMR1 premutation carriers, particularly in women, and how individual factors such as aging and CGG repeat length may contribute to changes in verbal inhibition over time. The present study examined verbal inhibition performance (i.e., inhibition errors) on the Hayling Sentence Completion Task in a cohort of 92 women with the FMR1 premutation across two timepoints approximately three years apart. We examined the effects of age, CGG repeat length, and their interactions on verbal inhibition over time. We also evaluated whether response latency affected verbal inhibition errors. We found no significant change in verbal inhibition in the full cohort during the three-year study period. However, a subset of FMR1 premutation carriers, namely older participants with higher CGG repeats, evidenced greater declines in verbal inhibition over time. Longer response latencies did not compensate for verbal inhibition errors. The findings suggest that a subset of women with the FMR1 premutation may be at earlier, increased risk for changes in executive functioning, which if confirmed, should be considered as part of the clinical profile associated with the premutation.

The Hybrid Assistive Limb (HAL; CYBERDYNE, Inc., Japan) is a wearable robot device that provides effective gait assistance according to voluntary intention by detecting weak bioelectrical signals of neuromuscular activity on the surface of the skin. We used HAL for patients with amyotrophic lateral sclerosis (ALS) to determine whether HAL training had an effect on their gait ability.

We conducted a single-center, single-arm, observational study. Patients with ALS underwent HAL training once per day (20-40min per session) for 9-10days for at least 4weeks. Gait ability was evaluated using the 2-minute walk test, the 10-meter walk test without the assistance of HAL, and activities of daily living (ADL) using the Barthel Index and Functional Independence Measures before and after a full course of HAL training.

There were no dropouts or adverse events during the observation period. Gait function improved after HAL training. The 2-minute walk test revealed a mean gait distance of 73.87m (36.65) at baseline and 89.