Notes

Rhoda-Electrocatalyzed C-H Methylation and Paired Electrocatalyzed C-H Ethylation along with Propylation.
Quorum sensing (QS) inhibition is one of the potential methods to target bacterial infection. In this study, comprehensive molecular dynamics simulation (MDS) experiments were conducted on the LasR structure to understand its structural dynamic behavior either in its ligand-free form or in its ligand-bound form (i.e. agonist or antagonist). The results revealed that LasR structure is significantly unstable in its ligand-free and antagonist-bound forms and such structural instability led eventually to complete dissociation of the functioning LasR dimeric form. Accordingly, twenty-eight benzimidazole derivatives were designed, synthesized as potential LasR antagonists, and characterized in vitro as QS inhibitors. Compounds 3d and 7f disclosed the highest percentage inhibition in biofilm formation, pyocyanin, and rhamnolipids production in Pseudomonas aeruginosa (71.70%, 68.70%, 54.00%) and (68.90%, 68.00%, 51.80%), respectively. MDS experiments revealed that these compounds as inhibitors, particularly, 3d, 7f, 8a, and 9g induce LasR structure instability and complete dissociation of its functioning dimeric form similarly to the previously reported inhibitor bromophenethyl-2-nitrobenzamide (BPNB). Furthermore, gene expression assays as another mechanism targeting quorum sensing genes to prove the inhibitory activity of these compounds on virulence factors, revealed that a number of the synthesized compounds were able to downregulate lasR (e.g. 3d and 7f by 61.70% and 26.00%, respectively) and rhlR (e.g. 7f by 16.30%) expressions. The results presented here provide a functional model for LasR that could guide future design of LasR inhibitors.Idiopathic pulmonary fibrosis (IPF) is a highly fatal disease that lacks appropriate treatments and highly effective drugs. Many reported indicated that the TGF-β1/Smad3 signaling pathway played a pivotal role in development of IPF. In this case, it was hypothesized that discovery novel compounds to block the TGF-β1/Smad3 signaling pathway might be useful for treatment of IPF. Therefore, a high-throughput screening system based on stably transfected CAGA-NIH3T3 cells was established for discovering lead compounds which could validly suppress the TGF-β1/Smad3 signal path. In this study, a series of novel Pleuromutilin derivatives were prepared and quickly evaluated by high-throughput assay. The lead compound 32 was discovered to be able to remarkably suppress the TGF-β1/Smad3 pathway in vitro. Further biological evaluation revealed that compound 32 could remarkably decrease the myofibroblast stimulation and extracellular matrix (ECM) deposition. More importantly, compound 32 could remarkably mitigate bleomycin (BLM)-triggered lung fibrosis in mice models. Additionally, the lead compound possess excellent pharmacokinetics properties, good oral availability and low toxicity. Benserazide in vivo In general, our study has demonstrated the potency of a novel Pleuromutilin derivative (compound 32), which might be a prospective candidate for developing anti-IPF medicines by suppress the TGF-β1/Smad3 signal pathway.MDM2 and MDM4 are key negative regulators of p53, an important protein involved in several cell processes (e.g. cell cycle and apoptosis). Not surprisingly, the p53 tumor suppressor function is inactivated in tumors overexpressing these two proteins. Therefore, both MDM2 and MDM4 are considered important therapeutic targets for an effective reactivation of the p53 function. Herein, we present our studies on the development of spiropyrazoline oxindole small molecules able to inhibit MDM2/4-p53 protein-protein interactions (PPIs). Twenty-seven potential spiropyrazoline oxindole dual inhibitors were prepared based on in silico structural optimization studies of a hit compound with MDM2 and MDM4 proteins. The antiproliferative activity of the target compounds was evaluated in cancer cell lines harboring wild-type p53 and overexpressing MDM2 and/or MDM4. The most active compounds in SJSA-1 cells, 2q and 3b, induce cell death via apoptosis and control cell growth by targeting the G0/G1 cell cycle checkpoint in a concentration-dependent manner. The ability of the five most active spiropyrazoline oxindoles in dissociating p53 from MDM2 and MDM4 was analyzed by an immunoenzymatic assay. Three compounds inhibited MDM2/4-p53 PPIs with IC50 values in the nM range, while one compound inhibited more selectively the MDM2-p53 PPI over the MDM4-p53 PPI. Collectively, these results show i) 3b may serve as a valuable lead for obtaining selective MDM2-p53 PPI inhibitors and more efficient anti-osteosarcoma agents; ii) 2a, 2q and 3f may serve as valuable leads for obtaining dual MDM2/4 inhibitors and more effective p53 activators.To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ1 receptor (σ1R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (Ki = 6.5 nΜ; EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED50 = 0.30 mg/kg, in mice). The contributions of MOR and σ1R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ1R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ1R ligands as a promising avenue for the development of potent and safe analgesics.Protein ubiquitination regulates almost all eukaryotic cellular processes, and is of very high complexity due to the diversity of ubiquitin (Ub) modifications including mono-, multiply mono-, homotypic poly-, and even heterotypic poly-ubiquitination. To accurately elucidate the role of each specific Ub signal in different cells with spatiotemporal resolutions, a variety of chemical biology tools have been developed. In this review, we summarize some recently developed chemical biology tools for ubiquitination studies and their applications in molecular and cellular biology.
To analyse the inter- and intra-examiner reliability for the neck flexion-rotation test and the C0-C2 axial rotation test when applied in asymptomatic subjects by two novice physiotherapists.

Repeated measures reliability study design. The study was approved by the Research Ethics Committee of [X], in compliance with the Declaration of Helsinki (CSEULS-PI 004/2020).

32 asymptomatic adults were included, recruited by convenience sampling. Two sessions were scheduled for each subject, with an intersession break of 30min. Two inexperienced raters blinded to their own previous and peer results performed three movements to both sides using the flexion-rotation test and the C0-C2 axial rotation test in randomised order of rater, test and direction. A third researcher collected the data measured by inertial sensors and displayed to the Pro Motion Capture software.

Both raters showed good-excellent intra-examiner reliability (ICC
ranging from 0.88 to 0.94) and moderate to good inter-examiner reliability (ICC
ranging from 0.58 to 0.86) to measure the rotation ROM with the FRT. The C0-C2 axial rotation test resulted in poor to moderate intra-examiner reliability (ICC
ranging from 0.33 to 0.74) and poor inter-examiner reliability using (ICC
ranging from 0.16 to 0.37).

Although performed by novice raters, the FRT showed good to excellent intra and inter-examiner reliability. Results for the C0-C2 axial rotation test were less reliable. We suggest that novice physiotherapists use the FRT instead of the C0-C2 axial rotation test in order to determine C1-C2 dysfunction.
Although performed by novice raters, the FRT showed good to excellent intra and inter-examiner reliability. Results for the C0-C2 axial rotation test were less reliable. We suggest that novice physiotherapists use the FRT instead of the C0-C2 axial rotation test in order to determine C1-C2 dysfunction.
Single Case Experimental Designs (SCEDs) are especially useful for small heterogeneous samples. Their role in evaluation of physiotherapy interventions for musculoskeletal conditions has not been systematically reviewed.

Systematically review use, purpose, and outcomes of SCEDs for physiotherapy interventions for musculoskeletal conditions.

Electronic databases and grey literature, searched using pre-defined terms.

Studies of human participants enrolled in eligible SCEDs (individual or a series).

We extracted study characteristics, analytic methods and results, synthesising these descriptively. We used RoBiN-T scale to assess risk of bias.

We included 19 SCEDs comprising 92 participants, with wide variability in design, methodology, analysis and in conditions and interventions evaluated. 95% of participants responded favourably to the tested intervention. Overall risk of bias was high, due to poor internal validity, especially regarding randomisation, blinding, inter-rater agreement and measurement of treatment adherence. Visual analysis alone was performed in 55% of studies. Assessment of provider and participant satisfaction was limited.

of key findings SCEDs may be well-suited to evaluation of physiotherapy interventions for musculoskeletal conditions, but the risk of bias in studies to date is high. Following SCED guidelines to minimize the risk of bias and maximise clinical usefulness is recommended.
of key findings SCEDs may be well-suited to evaluation of physiotherapy interventions for musculoskeletal conditions, but the risk of bias in studies to date is high. Following SCED guidelines to minimize the risk of bias and maximise clinical usefulness is recommended.
Left/right judgment task performance (LRJT) is impaired in severe neuropathic pain conditions. However, comparison of LRJT performance in patients with carpal tunnel syndrome (CTS) with a control group with similar cognitive functions has not been investigated.

The aim of the study was to compare the LRJT performance of CTS patients with healthy controls and the unaffected side.

Seventy-five CTS patients with dominant, right-hand involvement and 75 control subjects were included in the study. The Recognize® tablet application was used for LRJT performance. Tactile acuity (Two-point discrimination) and handgrip strength; pain severity (Visual Analog Scale) and neuropathic component of pain (Pain Detect Questionnaire); symptom severity and functional impact of CTS (Boston CTS Assessment Test) were evaluated. Mixed-design ANOVAs and correlation analyses were used for data analysis.

Cross-sectional study.

Analysis of variance showed that there was no significant effect of side (affected versus unaffected) or group (CTS versus control group) on recognition accuracy or time. Significant group*site interactions were found for the two-point discrimination F (1,148)=6.388, p=0.013; and for handgrip strength F (1,148)=17.552, p<0.01. A statistically significant negative correlation was found between recognition accuracy and symptom duration and a significant positive correlation was found between recognition accuracy and handgrip strength in CTS patients (r=-0.267, p=0.020; r=0.290, p=0.012).

CTS patients recognize the affected side as accurately and quickly as the unaffected side and control group. Further research is needed to clarify the relationship between LRJT performance in the severely affected CTS group.

NCT04967144 CLINICALTRIALS.

19 July 2021.
19 July 2021.
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