Search

Cannabinoid type 2 receptor (CB2R), belonging to the endocannabinoid system, is overexpressed in pathologies characterized by inflammation, and its activation counteracts inflammatory states. Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of the main endocannabinoid anandamide; thus, the simultaneous CB2R activation and FAAH inhibition may be a synergistic anti-inflammatory strategy. Encouraged by principal component analysis (PCA) data identifying a wide chemical space shared by CB2R and FAAH ligands, we designed a small library of adamantyl-benzamides, as potential dual agents, CB2R agonists, and FAAH inhibitors. The new compounds were tested for their CB2R affinity/selectivity and CB2R and FAAH activity. Derivatives 13, 26, and 27, displaying the best pharmacodynamic profile as CB2R full agonists and FAAH inhibitors, decreased pro-inflammatory and increased anti-inflammatory cytokines production. Molecular docking simulations complemented the experimental findings by providing a molecular rationale behind the observed activities. These multitarget ligands constitute promising anti-inflammatory agents.

Background: The prospective DIabetes and CATaract Study II (DICAT II) was performed to characterise the risks of cataract surgery to the retinae of patients with early diabetic macular oedema (E-DMO). Methods: DICAT II was a prospective, comparative, multicentre, observational study involving six Italian clinics. Patients were aged ≥55 years, had type 1 or 2 diabetes with spectral-domain optical coherence tomography evidence of ESASO classification Early DMO. Group 1 eyes (78 eyes, 78 patients) underwent phacoemulsification-based cataract surgery. Group 2 eyes (65 eyes, 65 patients) had E-DMO and either clear media or had undergone uncomplicated cataract surgery ≥1 year previously. Central subfield thickness (CST) and best-corrected visual acuity (BCVA) were assessed in both groups. Results: The negative impact of surgery on CST was evident after the first postoperative week; CST peaked during the first month, then rapidly decreased. CST worsening ≥10 µm was observed in 63/78 eyes (80.7%) and 29/65 eyes (44.6%) in Groups 1 and 2, respectively (p< 0.0001). CST worsening of ≥50 µm was observed in 51 eyes (65.4%) and 10 eyes (15.4%) in Groups 1 and 2, respectively (p< 0.0001). Mean CST worsening was lower in Group 2 than in Group 1 (38.6 ± 30.4 µm vs 85.5 ± 55.3 µm, p< 0.0001) with a lower BCVA loss (−2.6 ± 3.5 letters vs −8.2 ± 6.2 letters, p< 0.0001). Higher glycaemic levels and HBA1c levels were significantly associated with the risk of >50 μm CST worsening in eyes from both groups. Conclusion: Early DMO is associated with poorer outcomes after cataract surgery and requires close pre- and postoperative monitoring.

Byline: Roberto Saviano In every place and every era--from ancient China to East Germany--walls have created fractures, divisions, injustice. So when a politician announces the construction of a wall, the [...]

The knowledge of emergency contraception among adult women of reproductive age at risk of pregnancy was examined. Results reveal that thirty-eight percent of California women correctly identified emergency contraception.

Background: Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant’s intake. Anticoagulants are commonly used for the prevention and treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, and betrixaban) showed better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. Methods: We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. Aim: This review summarizes the current evidence about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with active major bleeding or who need urgent surgery which physicians indicate for a better management approach in order to increase patient’s safety. Conclusion: Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

Country crooner Wills finds lots of good things to celebrate in his life. He has a successful career as evidenced by his gold album, 'Wish You Were Here.' He has a new home in Atlanta, GA. Most importantly, he has a beautiful wife and a cuddly, newborn baby girl.

Country singer Carter is proud that the influence of the 1970s decade shows in her new album called 'Everything's Gonna Be Alright.' In preparation for the recording, her studio was decorated with things that reminded her of the 1970s. She calls herself a '70s kid, not a generation X-er.

Byline: Roberto Saviano A video showing the hideout of Joaquin Guzman Loera (aka 'El Chapo'), filmed October 6 by the Mexican navy and broadcast by the Mexican newspaper El Universal, [...]

The modern forehand technique in tennis has developed as a result of better racquets, changes in court surfaces, and stronger athletes. The technique, which is practiced by players such as Martina Hingis, Gustavo Kuerten, and Pete Sampras, is explained in detail.

A survey conducted by the Computer Sciences Corp. reveals that there is an increasingly important relationship between technology and corporate strategy. Some trends in information technology management include more outsourcing of IT functions and developing enterprise-wide systems.

Many great tennis players know how to anticipate their opponents' moves and return their opponents' shots. Faster response time as a result of good anticipation gives tennis players a distinct advantage over their opponents. Tips on how to anticipate an opponent's moves are presented.

Drug-induced blockade of the human ether-à-go-go-related gene (hERG) channel is today considered the main cause of cardiotoxicity in postmarketing surveillance. Hence, several ligand-based approaches were developed in the last years and are currently employed in the early stages of a drug discovery process for in silicocardiac safety assessment of drug candidates. Herein, we present the first structure-based classifiers able to discern hERGbinders from nonbinders. LASSO regularized support vector machines were applied to integrate docking scores and protein–ligand interaction fingerprints. A total of 396 models were trained and validated based on: (i) high-quality experimental bioactivity information returned by 8337 curated compounds extracted from ChEMBL (version 25) and (ii) structural predictor data. Molecular docking simulations were performed using GLIDE and GOLD software programs and four different hERGstructural models, namely, the recently published structures obtained by cryoelectron microscopy (PDB codes: 5VA1 and 7CN1) and two published homology models selected for comparison. Interestingly, some classifiers return performances comparable to ligand-based models in terms of area under the ROC curve (AUCMAX= 0.86 ± 0.01) and negative predictive values (NPVMAX= 0.81 ± 0.01), thus putting forward the herein proposed computational workflow as a valuable tool for predicting hERG-related cardiotoxicity without the limitations of ligand-based models, typically affected by low interpretability and a limited applicability domain. From a methodological point of view, our study represents the first example of a successful integration of docking scores and protein–ligand interaction fingerprints (IFs) through a support vector machine (SVM) LASSO regularized strategy. Finally, the study highlights the importance of using hERGstructural models accounting for ligand-induced fit effects and allowed us to select the best-performing protein conformation (made available in the Supporting Information, SI) to be employed for a reliable structure-based prediction of hERG-related cardiotoxicity.

Byline: EVA SAVIANO JOSEPH EINHORN, 32 CEO, FANCY.COM It was after a trip to London that Joseph Einhorn decided to name his website Fancy.com, a nod to digging something--a rather [...]

Byline: EVA SAVIANO TWENTY MINUTES, 10 SECONDS. That's the time it took for James Grooms, 46, to sprint 1,576 stairs to the 86th-floor observation deck in the 37th Empire State [...]

Byline: EVA SAVIANO Tani USA: Adam Dinkes, 40, joined the luxury underwear brand as president and chief executive. He was previously chief operating officer at Sadick Dermatology. FEGS Health and [...]

Byline: EVA SAVIANO COMPANY SPOTLIGHT DIANE VON FURSTENBERG STUDIO #48 DIANE VON FURSTENBERG signs many of her tweets 'Love, Diane.' The mother of the iconic wrap dress--celebrating its 40th anniversary [...]

Byline: EVA SAVIANO Water Waste Prevention Inc.: Jonathan Mantell, 34, joined the real estate support services company as chief operating officer, a newly created position. He was previously director of [...]

Bioconjugates of 2,1,3-benzoxadiazole (benzofurazan) and its derivatives have attracted considerable interest due to their biological activities and applications as fluorescent tags. A high-yield, chemoselective, and mild procedure for the S-alkylation of cysteine containing peptides by benzofurazan halogenides is reported. The key feature of this procedure is the use of activated molecular sieves (MS) to catalyze thiol activation for nucleophilic substitution under very mild conditions (room temperature and no need for added bases). To the best of our knowledge, this is the first report about thiol nucleophilic substitution performed on unsaturated and annelated systems catalyzed by activated molecular sieves. Reaction yields were remarkable even with benzofurazans having weakly activating groups or no activating groups at all. The potential of the new methodology was explored by synthesizing fluorescent, hydrophilic benzofurazan/peptide conjugates, also with peptides containing unprotected lysine residues.

ObjectiveHepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.DesignLiver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivoand ex vivovalidation were used to identify chromatin modifiers and readers for HCC chemoprevention.ResultsIn patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.ConclusionOur results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.

A short (Fab)trastuzumab-derived peptide specific for HER2 receptor was identified. Its affinity for the model system HER2-DIVMP was found in a nanomolar range. The structural determinants responsible for the interaction between this ligand (A9) and HER2-DIVMP were investigated by both computational and NMR analysis. Next, the possibility of using A9 as HER2- specific probe for the nuclear medicine imaging was evaluated by conjugating A9 with the DTPA chelator and radiolabeling it with 111In. The developed probe retained a nanomolar affinity to HER2-overexpressing cancer cells, however, some unspecific binding also occurred. The peptide internalization into cells by receptor-mediated endocytosis was also studied. Future perspectives are aimed at using A9 as a probe for molecular imaging diagnostics as well as active targeting of anticancer drugs. Lead structure optimization is needed to minimize the percentage of A9 unspecific binding and to increase the binding affinity to the receptor.

Kersh has become one of country music's hottest heartthrobs. Since releasing his debut album 'Goodnight Sweetheart' in 1996, the young texan balladeer has posted four Top 10 hits and has attracted the feverish devotion of hordes of female fans.

Becoming a strong clay-court player takes good movement and footwork, physical conditioning and endurance, and the brains to know when to go for your shots. The predominant surface in the […]

Ketchum's album entitled 'Hal, Yes' has been retitled as 'Awaiting Redemption' by his record company, Curb Records. The album was first scheduled to be released in 1997 but was shelved. The songs reflect his past problem with alcohol and drugs and his bout with acute transverse myelitis.

Tennis matches with less-skilled players offers an opportunity for one to work on weaknesses and improve. Against weaker opponents, baseliners can concentrate on their serve-and-volley game while those who usually attack the net can operate from the baseline.

Purpose: To describe two cases of Cobb’s tufts in apparently healthy subjects.Methods: Observational case series.Results: Two patients reporting sudden vision loss, with subsequent complete recovery, underwent a complete ophthalmological examination, including iris fluorescein angiography. Both patients took an “eye-selfie” using their smartphone to provide evidence of the iris bleeding. Iris fluorescein angiography confirmed the presence of iris neovascular tufts at the pupillary margin.Conclusion: Diagnosis of Cobb’s tufts can frequently be challenging. The two patients’ astute action in taking photographs of the eye enabled the condition to be promptly identified.

AbstractShwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder whose patients present mutations in two ribosome assembly proteins, the Shwachman-Bodian-Diamond Syndrome protein (SBDS) and the Elongation Factor-Like 1 (EFL1). Due to the lack of knowledge of the molecular mechanisms responsible for SDS pathogenesis, current therapy is nonspecific and focuses only at alleviating the symptoms. Building on the recent observation that EFL1 single-point mutations clinically manifest as SDS-like phenotype, we carried out comparative Molecular Dynamics (MD) simulations on three mutants, T127A, M882K and R1095Q and wild type EFL1. As supported by small angle X-ray scattering experiments, the obtained data improve the static EFL1 model resulting from the Cryo-electron microscopy and clearly show that all the mutants experience a peculiar rotation, around the hinge region, of domain IV with respect to domains I and II leading to a different conformation respect to that of wild type protein. This study supports the notion that EFL1 function is governed by an allosteric mechanism involving the concerted action of GTPase domain (domain I) and the domain IV and can help point towards new approaches to SDS treatment.Communicated by Ramaswamy H. Sarma

The attentional spatial-numerical association of response codes (Att-SNARC) effect (Fischer, Castel, Dodd, & Pratt, 2003)—the finding that participants are quicker to detect left-side targets when the targets are preceded by small numbers and quicker to detect right-side targets when they are preceded by large numbers—has been used as evidence for embodiednumber representations and to support strong claims about the link between number and space (e.g., a mental number line). We attempted to replicate Experiment 2 of Fischer et al. by collecting data from 1,105 participants at 17 labs. Across all 1,105 participants and four interstimulus-interval conditions, the proportion of times the effect we observed was positive (i.e., directionally consistent with the original effect) was .50. Further, the effects we observed both within and across labs were minuscule and incompatible with those observed by Fischer et al. Given this, we conclude that we failed to replicate the effect reported by Fischer et al. In addition, our analysis of several participant-level moderators (finger-counting habits, reading and writing direction, handedness, and mathematics fluency and mathematics anxiety) revealed no substantial moderating effects. Our results indicate that the Att-SNARC effect cannot be used as evidence to support strong claims about the link between number and space.

Byline: EVA SAVIANO BY THE END OF 2014, visitors to the High Line will be able to walk the entirety of the salvaged railroad line turned park, from Gansevoort to [...]

Byline: EVA SAVIANO DOREEN LORENZO knows a little something about product development. After 16 years at technology design and engineering firm frog--seven as its president--Ms. Lorenzo has jumped into social [...]

Byline: EVA SAVIANO BRITAIN, FRANCE, HOLLAND, ASIA. Robert Naylor's career in the food and beverage industry has taken him many places. Now it brings him to New York. The new [...]

Byline: EVA SAVIANO ELECTION SEASON may be upon us, but that doesn't mean average voters have a clue about the candidates--or the jargon that they must translate to make sense [...]

Byline: EVA SAVIANO THE OPPORTUNITY TO INDULGE different aspects of herself drew former Google Senior Counsel Anjali Kumar, 40, to rapidly growing Warby Parker as the eyewear e-tailer's first general [...]

Byline: EVA SAVIANO BEGINNING JULY 1, WILLIAM P. KELLY, 63, currently president of City University of New York's Graduate Center, will become the school's interim chancellor following Matthew Goldstein's nearly [...]

Byline: EVA SAVIANO IN FIVE YEARS as president of U.K.-based Pret A Manger, Martin Bates grew the grab-and-go eatery chain from 11 stores in New York City to 51 along [...]

Byline: EVA SAVIANO A NEW CFO FOR WEBSITE'S NEW PHASE THERE ARE TWO TYPES OF CFOS, said Justin Stefano, co-founder of Refinery29, a style and design website that began as [...]

Byline: EVA SAVIANO RHYS POWELL,33 President and founder, RED RABBIT Rhys Powell says memories of growing up in the Bahamas inspired him to quit his stock-trading job and launch his [...]

Byline: EVA SAVIANO MARK HURWITZ brings years of real estate development and government policy experience to his new job as president and chief executive of Palladia Inc., a nonprofit aiding [...]

Byline: EVA SAVIANO LORI HOCK considers herself lucky to work for her boss, Manolo Marquez, chief executive of Hudson Global Inc., a high-end talent management and acquisition company. 'He provides [...]

Byline: EVA SAVIANO PEEQ MEDIA, a New York-based media-production company that creates and prints billboards, in-store display signs and paper goods, knows that in order to stay relevant, it has [...]

Byline: Eva Saviano American Academy of Matrimonial Lawyers: Alton Abramowitz, 64, was promoted to president of the organization. He was previously vice president. TheLadders: Alexandre Douzet, 38, was promoted to [...]