Elucidating the Mechanism of Tetrahydrofuran-Diol Formation through Os(VI)-Catalyzed Oxidative Cyclization of 5,6-Dihydroxyalkenes Ligated by Citric Acid.

A computational study is reported here on the mechanism of tetrahydrofuran (THF)-diol formation from the Os(VI)-catalyzed oxidative cyclization of 5,6-dihydroxyalkene ligated with citric acid and in the presence of BroÌ·nsted acid. Initiated by Os(VI) dioxo citrate formation, coordination of co-oxidant pyridine-N-oxide (PNO) and protonation of its oxo group generate the active catalyst. The catalytic cycle commences through successive steps, including dihydroxyalkene addition to the active catalyst in a concerted mechanism to form hexacoordinated alkoxy-protonated PNO-complexed Os(VI) bisglycolate as a turnover-limiting step (TLS), cyclization to Os(IV) THF-diolate, reoxidation to Os(VI) THF-diolate, and hydrolysis via a dissociative mechanism to furnish the THF-diol and regenerate the active species, sustaining the catalytic cycle through an Os(VI)/Os(IV) cycle. Despite the overall exergonic nature of catalytic cycle (ΔGrcycle = -45.0 kcal/mol), the TLS is accelerated by the formation of an open-valence 16-electron Os(VI) intermediate but decelerated by the undesired formation of a saturated/hexacoordinate 18-electron Os(VI) intermediate. BroÌ·nsted acid plays crucial roles in the formation of Os(VI) citrate and the active catalyst, impediment of the second cycle, and the cyclization step. Additionally, besides its role as a co-oxidant, and in the presence of acid, PNO is found to assist the insertion of dihydroxyalkene and, importantly, in releasing the THF-diol to regenerate the active intermediate.

Remote Steric and Electronic Effects of N-Heterocyclic Carbene Ligands on Alkene Reactivity and Regioselectivity toward Hydrocupration Reactions: The Role of Expanded-Ring N-Heterocyclic Carbenes.

The remote groups in N-heterocyclic carbene (NHC) ligands have a significant influence on metal-catalyzed reactions. We examine how remote bulkiness, electronic groups, and expanded-ring NHCs (ER-NHCs) influence alkene reactivity and regioselectivity toward hydrocupration using density functional theory calculations. The impact of remote steric bulkiness on the Cu-H insertion rate is analyzed, revealing a strong correlation between the steric substituent constant and rate ratio, where a bulky group increases the rate due to reduced steric effects in the transition state (TS). The steric properties of the examined catalysts (with a remote group R2 = CPh3, CHPh2, CH2Ph, CH3, and H) and their corresponding TSs are found to be modulated greatly by the remote steric substitution group and the ring size of the NHC ligand. Enhanced bulkiness enhances the nucleophilic Cu-H moiety. The remote electronic groups have a smaller impact on insertion barrier compared to that of steric hindrance. Furthermore, ER-NHC exploration indicates that NHCs with over five-membered rings have a significantly negative influence on the reaction rate. Finally, with a highly bulky group (R2 = CPh3), anti-Markovnikov insertion preference is attributed to high interaction energy and improved steric properties. Overall, our findings here provide valuable insights for the development of a more effective catalyst in metal-catalyzed reactions.

Partner effect in accelerating pincer-co catalyzed nitrile hydroboration reactions.

The pincer-Co catalyzed nitrile hydroboration of nitrile has been presented as an elegant strategy to afford amine synthesis; however, ligand engineering is required. We show here a strategy to tune the catalytic behavior of the organometallic catalyst, as an alternative approach to ligand engineering, by means of computational investigations to understand the effect of partners such as (18-crown-6)K+, W(CO)3 and W(PMe3)3 on the reactivity of the pincer-Co catalyzed nitrile hydroboration reaction through π-coordination to the ligand aromatic ring. The extra additives bind the central phenyl ring of the ligand by either dispersion or chemical bonding. The electron-richness of the cobalt center is tuned by the partner, and follows the order (18-crown-6)K+ > W(PMe3)3 > no partner > W(CO)3. While the influence of the covalent W-containing partners parallels the electron-richness of the W, the non-covalent partner, (18-crown-6)K+, surprisingly increases the donor ability of the pincer ligand through the polarization effect. All the elementary steps involved in the nitrile hydroboration reaction are influenced by the partner, and the overall barrier is lowered by a surprisingly large amount of 4.9 kcal mol-1 in the presence of (18-crown-6)K+, suggesting a notable partner effect to be explored by experimentalists so that the reactivity of a catalyst can be tuned without ligand modification.

Boosting Palladium-Catalyzed Aryl-Nitro Bond Activation Reaction by Understanding the Electronic, Electrostatic, and Polarization Effect: A Computational Study from a Basic Understanding to Ligand Design.

Although palladium-catalyzed aryl-nitro bond activation reaction has recently gained a lot of interest, it still requires rather harsh conditions. We here systematically explore the substituent effect on oxidative addition steps, known as the rate-determining step, by density functional theory simulations based on a Nakao's nitrogen heterocyclic carbene (NHC) ligand. The key aryl ring on the catalyst, ring A, acts as a π-donor and stabilizes the palladium center of the transition state, and thus an electron-rich ring A is expected to lower the barrier. However, the polarization and electrostatic effects were shown to be more important, although they were often ignored before. These effects originate from through-space interaction with a nitro group in the resting state, and the overall effect is that any polarizable or partly negative group near ortho- or meta-site of ring A is harmful for the reaction. Based on these discoveries, we proposed a list of guidelines for successful ligand developments and designed several new ligands. These ligands exhibit a significantly lower barrier than the reported Nakao's ligand by as large as ∼5 kcal/mol, in both gas phase and solvent with a moderate dipole. These candidates will promote further experimental studies and enhance the ability to improve ligands in a rational and predictive manner.

Chiral surface spin textures in Cu2OSeO3 unveiled by soft X-ray scattering in specular reflection geometry.

Resonant elastic soft X-ray magnetic scattering (XRMS) is a powerful tool to explore long-periodic spin textures in single crystals. However, due to the limited momentum transfer range imposed by long wavelengths of photons in the soft x-ray region, Bragg diffraction is restricted to crystals with the large lattice parameters. Alternatively, small-angle X-ray scattering has been involved in the soft energy X-ray range which, however, brings in difficulties with the sample preparation that involves focused ion beam milling to thin down the crystal to below a few hundred nm thickness. We show how to circumvent these restrictions using XRMS in specular reflection from a sub-nanometer smooth crystal surface. The method allows observing diffraction peaks from the helical and conical spin modulations at the surface of a Cu   2 OSeO   3 single crystal and probing their corresponding chirality as contributions to the dichroic scattered intensity. The results suggest a promising way to carry out XRMS studies on a plethora of noncentrosymmetric systems hitherto unexplored with soft X-rays due to the absence of the commensurate Bragg peaks in the available momentum transfer range.

Surgical aortic valve replacement in small aortic annulus.

BACKGROUND: Although aortic valve replacement (AVR) has been the standard of treatment for severe aortic stenosis, a small aortic annulus (SAA) poses significant challenges. Improvements in valve designs and evolution in surgical techniques have led to improved outcomes, however, the ideal prosthetic valve remains elusive. METHODS: We performed a comprehensive literature review to discuss the surgical management of aortic stenosis, with a special focus on patients with SAA. RESULTS: Stentless valves and root replacement techniques have been shown to overcome the hemodynamic challenges associated with conventional stented bioprostheses, but are technically challenging and require longer cross-clamp times. Sutureless and rapid deployment valves mitigate the long operative time while maintaining the hemodynamic advantages. The use of transcatheter AVR has emerged as another reasonable alternative and has shown promise among patients with SAA, however, long-term outcomes are awaited. CONCLUSION: There is no consensus regarding the type of valve prosthesis or replacement technique among patients with SAA. Consideration of patient comorbidities and valvular anatomy is paramount in planning the optimal strategy for AVR. Further long-term clinical trials are necessary to assess outcomes and achieve progress toward the development of the ideal prosthesis.

Revealing the Mechanism and Origin of Reactivity of Au(I)-Catalyzed Functionalized Indenone Formation of Cyclic and Acyclic Acetals of Alkynylaldehydes.

A density functional theory study is presented here to offer mechanistic insights and explications of experimentally intriguing observations in the Au(I)-catalyzed cyclization of cyclic and acyclic acetals of alkynylaldehydes that leads to indenone formation. The reactivity of catalytic cycles with and without methoxy migration is clearly defined when the alkyne terminus is phenylated. The reaction mechanism of indenone formation proceeds first with the coordination of Au(I) to alkyne to initiate the reaction with 1,5-H shift as a rate-determining step (RDS), and the fastest 1,5-H shift is achieved when one phenyl ring carries an electron-donating group and the other one is substituted with an electron-withdrawing group. Following the 1,5-H shift, the reaction undergoes feasible steps that are cyclization and 1,2-H shift before elimination to persist the iterative cycle, but the reactivity of both steps is highly affected by the existence of the phenyl group on the alkyne terminus. The unreactivity of the alkyne terminus not bearing a phenyl ring is because the cyclization is thermodynamically disfavorable, subsequently deactivating the 1,2-H shift kinetically and thermodynamically. The absence of a tether in the acetal unit considerably outpaces any 1,5-H shift and instead activates 1,5-methoxy migration, giving methoxy-migrated indenone, with the 1,2-OMe shift being an RDS.

Ferromagnetic Resonance with Magnetic Phase Selectivity by Means of Resonant Elastic X-Ray Scattering on a Chiral Magnet.

Cubic chiral magnets, such as Cu_{2}OSeO_{3}, exhibit a variety of noncollinear spin textures, including a trigonal lattice of spin whirls, the so-called skyrmions. Using magnetic resonant elastic x-ray scattering (REXS) on a crystalline Bragg peak and its magnetic satellites while exciting the sample with magnetic fields at gigahertz frequencies, we probe the ferromagnetic resonance (FMR) modes of these spin textures by means of the scattered intensity. Most notably, the three eigenmodes of the skyrmion lattice are detected with large sensitivity. As this novel technique, which we label REXS FMR, is carried out at distinct positions in reciprocal space, it allows us to distinguish contributions originating from different magnetic states, providing information on the precise character, weight, and mode mixing as a prerequisite of tailored excitations for applications.

Mechanism of Os-Catalyzed Oxidative Cyclization of 1,5-Dienes.

The oxidative cyclization of 1,5-dienes by metal-oxo species is a powerful method for stereocontrolled synthesis of tetrahydrofuran diols (THF-diols), structural motifs present in many bioactive natural products. Oxidative cyclization of (2E,6E)-octa-2,6-diene catalyzed by OsO4/NMO has been studied using density functional theory (DFT) calculations (M06-2X/aug-cc-pVDZ/Hay-Wadt VDZ (n+1) ECP), highlighting the remarkable effect of acid on the fate of the first intermediate, an Os(VI) dioxoglycolate. A strong acid promotes cyclization of the Os(VI) dioxoglycolate, or its NMO complex, through protonation of an oxo ligand to give more electrophilic species. By contrast, in the absence of acid, reoxidation may occur to afford the Os(VIII) trioxoglycolate, which is shown to favor conventional "second cycle" dihydroxylation reactivity rather than cyclization. The results of the calculations are consistent with experimental results for reactions of OsO4/NMO with 1,5-dienes with acid (oxidative cyclization) and without acid (second cycle osmylation/dihydroxylation). Detailed evaluation of potential catalytic cycles supports oxidation of the cyclized Os(IV) THF-diolate intermediate to the corresponding Os(VI) species followed by slow hydrolysis and, finally, regeneration of OsO4.

Kuwait association of rheumatology 2018 treatment recommendations for patients with rheumatoid arthritis.

The Kuwait Association of Rheumatology (KAR) aimed to develop a set of recommendations for the treatment of patients with rheumatoid arthritis (RA), tailored to the unique patient population and healthcare system of Kuwait. Each recommendation was developed based on expert opinion and evaluation of clinical practice guidelines from other international and national rheumatology societies. Online surveys were conducted to collate feedback on each KAR member's level of agreement (LoA) with definitions of disease-/treatment-related terms used and the draft recommendations. Definitions/recommendations achieving a pre-defined cut-off value of ≥ 70% agreement were accepted for inclusion. Remaining statements were discussed and revised at a face-to-face meeting, with further modifications until consensus was reached. A final online survey was used to collect feedback on each KAR member's LoA with the final set of recommendation statements on a scale of 0 (complete disagreement) to 10 (complete agreement). Group consensus was achieved on 66 recommendation statements, including 3 overarching principles addressing the pharmacological treatment and management of RA. Recommendations focused on treatment of early RA, established RA, patients with high-risk comorbidities, women during pregnancy and breastfeeding, and screening and treatment of opportunistic infections. The KAR 2018 Treatment Recommendations for RA reported here are based on a synthesis of other national/international guidelines, supporting literature, and expert consensus considering the Kuwaiti healthcare system and RA patient population. These recommendations aim to inform the clinical decisions of rheumatologists treating patients in Kuwait, and to promote best practices, enhance alignment and improve the treatment experience for patients.

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies.

Retinal dystrophies (RDs) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multigene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also show the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including one deep intronic and one genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will probably account for only a minor role in the mutation burden.

Communicating printed headings to the ear.

Two experiments compared three methods of translating printed headings into an auditory format. In both experiments, college students listened to a text with instructions to stop the recording whenever they heard a heading and type the hierarchical level and exact wording of the heading. Listeners were poor at identifying headings and their levels if the headings were not distinguished from the rest of the text. However, listeners were very good at identifying headings if any method of signalling was used to distinguish headings and communicate their hierarchical level. The methods included: (1) tones preceding headings, (2) changes of speaker to indicate headings or (3) verbal labels preceding headings. Although all three signalling methods improved identification of a heading's hierarchical level, the labelling method was the most effective means of communicating hierarchical level. Thus, the study identifies a simple method of effectively communicating headings in spoken text. Practitioner Summary: The study attempted to identify effective ways of communicating heading information in spoken text. College students listened to texts in order to detect headings and record their wording and hierarchical level. Performance was excellent when headings were preceded by verbal phrases that signalled the upcoming headings and their levels.

Influence of HumDN1 VNTR polymorphism on DNASE1 expression in systemic lupus erythematosus and rheumatoid arthritis.

The purpose of this study was to analyze the effect of the HumDN1 VNTR polymorphism on DNASE1 mRNA expression and enzyme activity in lupus (SLE) and rheumatoid arthritis (RA) compared to healthy control (HC). Kuwait subjects (n = 500) matched by age/gender/ethnicity were genotyped by fragment-analysis. DNASE1 expression was analysed using quantitative Real-Time-PCR and sera from subjects were screened for DNase1 reduction activity by ELISA. Allele and genotype distribution of HumDN1 VNTR revealed a significant association with susceptibility to SLE and RA (p < 0.05, OR > 1). Relative expression analysis revealed a significant increase in DNASE1 mRNA in SLE (p = 0.0001) and RA (p = 0.002) compared to HC. Stratification of subjects revealed, increased DNASE1 expression in SLE with 5/5 (p = 0.0001), 3/4 (p = 0.0001) and 3/5 genotype (p = 0.01). A reduction in DNASE1 expression was specifically observed in SLE with 4,4 genotype (p = 0.0004). RA patients with 3/4 genotype (p = 0.02) showed a significant increase in DNASE1 expression. Similarly a significant association was observed between DNase1 reduction activity and SLE (p = 0.0001). SLE patients with 3,4 (p = 0.0001) and 5,5 genotype (p = 0.0001) showed increased DNase1 reduction activity, while a lack of association was observed with RA. The present study is the first to reveal the effect of HumDN1 VNTR on DNASE1 expression in SLE and RA.

Risk-Based Approach for Defining Retest Dates for Active Pharmaceutical Ingredients and Excipients.

Drug substances and excipients must be stored in recommended storage conditions and should comply with their specifications during the retest period for their use in the manufacture of drug products. The ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) and WHO (World Health Organization) regulatory guidelines mandate that after the retest period, the drug substances must be retested for compliance with the specification and then used immediately in the manufacture of the finished product. Although these substances can be retested multiple times, an emphasis is placed on immediate use following a retest and compliance with standards. The phrase "used immediately" is ambiguous and is left for interpretation. In this article, we will look at the various processes that must be completed to determine the retest date. In addition, we present a risk-based method for establishing retest dates and the time during which material can be used.

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.

Impact of counteranions on N-heterocyclic carbene gold(i)-catalyzed cyclization of propargylic amide.

N-Heterocyclic carbene (NHC) Au(i)-catalyzed organic synthesis has recently been receiving increasing attention, especially with the activation of alkynes. In contrast, counteranions, being widely problematic in Au(i)-catalyzed transformations, are commonly considered as innocent partners and are not respectably included in a computational model. Herein, we report density functional theory (DFT) investigations of the Au(i)-catalyzed cyclization of propargylic amides to exploit the mechanistic effect of several counteranions to shed some light for further future developments. Among the counteranions used in this study, NTf2 -, ClO4 -, TsO-, TFA-, TfO-, MsO-, and SbF6 -, both the cyclization and protodeauration step favor the 5-exo-dig product over the 6-endo-dig product when the alkyne moiety is terminated with hydrogen. These anions reveal a crucial influence on the energy profile through lowering the barriers of the reaction. Mechanistically, the results obtained from all counteranions show that the protodeauration is slower than the cyclization. By using an energetic span model, the results clearly indicate that the rate-determining state is the protodeauration step for all counteranions, and thus protodeauration is the turnover-limiting step. The turnover frequency (TOF) results for the formation of the 5-exo-dig product show cyclization reactivity in the order of MsO- > TFA- > ClO4 - > NTf2 - > TfO- > TsO- ≫ SbF6 -, whereas an order of TFA- > MsO- > NTf2 - > TfO- ≈ ClO4 - > SbF6 - ⋙ TsO- is calculated for the protodeauration, suggesting that SbF6 - and TsO- are disfavored due to their slow protodeauration. In this regard, and for the 6-endo-dig pathway, our conclusions demonstrate an order of TfO- > TFA- > MsO- > NTf2 - > ClO4 - > TsO- ⋙ SbF6 - for the cyclization and TFA- > TsO- > MsO- > TfO- > NTf2 - > ClO4 - ⋙ SbF6 - for the protodeauration, advocating that the anions SbF6 -, NTf2 - and ClO4 - are unlikely partners for the 6-endo-dig pathway because of their slow protodeauration. Finally, the findings here advise that any engineering of the counteranion to increase the efficiency of catalytic system would be more effective on the protodeauration step rather than the cyclization step.

Design of a Compact Quad-Channel Microstrip Diplexer for L and S Band Applications.

In this paper, two novel dual-band bandpass filters (BPFs) and a compact quad-channel diplexer working at 1.7/3.3 GHz and 1.9/3.6 GHz are proposed. In the proposed diplexer design, triangular loop resonators and rectangular loop resonators are used together to reduce the circuit size and improve diplexer performances. Insertion loss (IL) and return loss (RL) of the proposed diplexer are better than 0.8 dB and 21 dB, respectively, at these four operating frequencies. Output ports isolation parameter is better than 30 dB. With the achieved specifications, the proposed diplexer can be used in L and S band applications.

Adult Knowledge About Postoperative Complications of Rhinoplasty in the Western Region of Saudi Arabia.

Background Rhinoplasty, a prevalent cosmetic surgical procedure worldwide, is not exempt from associated risks and complications, as with any other surgery. In light of the surging demand for rhinoplasty amongst young adults, it is imperative to acknowledge that the procedure can engender various complications that can be classified as either early or late complications. Examples of early complications include epistaxis and periorbital ecchymosis, while late complications may manifest as enophthalmos or septal perforation. The present study endeavors to gauge the knowledge of rhinoplasty complications among adult residents of the Western region of Saudi Arabia. Methods To achieve the research objectives, a cross-sectional study design was implemented, utilizing a self-administered online questionnaire. The study targeted male and female adults aged 18 years and above residing in the Western region of Saudi Arabia. The questionnaire comprised of 14 items, categorized into socio-demographic and rhinoplasty postoperative complications sections, respectively. Results The study gathered responses from a total of 968 participants, of which 60.95% fell within the age range of 18-30 years. The majority of participants identified as female (77.89%), and Saudi citizens constituted the vast majority of the respondents (96.28%). Among the participants, 22.62% expressed a desire to undergo rhinoplasty, whereas 77.38% indicated no interest in the procedure. Of those who sought rhinoplasty, the majority favored having the surgery performed by a skilled physician (81.74%). Notably, participants exhibited a relatively high level of awareness regarding the postoperative complications of rhinoplasty, with respiratory issues being the most widely recognized complication (66.63%). Conversely, headache, nausea, and vomiting were the least familiar complications (100%). Conclusion The study findings reveal a considerable knowledge gap among adults residing in the Western region of Saudi Arabia concerning rhinoplasty's possible postoperative complications. The results underscore the pressing need to establish comprehensive educational and awareness-raising programs to equip individuals contemplating the procedure with the requisite information to make informed decisions. Future research endeavors could delve into the underlying determinants that drive the desire for rhinoplasty and assess potential interventions geared toward augmenting individuals' comprehension and knowledge of the procedure.

Expert Opinion Guidance on the Detection of Early Connective Tissue Diseases in Interstitial Lung Disease.

There is a significant variation in symptoms and clinical presentation of connective tissue disorders (CTD) associated with interstitial lung disease (ILD) (CTD-ILD). This presents difficulties in the diagnosis and treatment of CTD-ILD. Early detection and treatment of CTD-ILD using a multidisciplinary approach have been shown to enhance patient outcomes. This exercise aims to explore clinical components to develop a screening tool for pulmonologists for early detection of CTD in ILD and to provide a framework for a multidisciplinary approach in managing CTD-ILD. This in turn will lead to early treatment of CTD-ILD in collaboration with rheumatologists. A panel of 12 leading rheumatologists from the Middle East and North Africa (MENA) region met virtually to select the most relevant clinical findings to aid in identifying CTD-ILD. Twelve panellists opted to investigate seven of the most common inflammatory autoimmune disorders. The panel discussed how to improve the early detection of CTD-ILD. Clinical characteristics were categorized, and a nine-item questionnaire was created. A biphasic algorithm was developed to guide early referral to a rheumatologist based on the presence of one of nine clinical features of CTD (Phase 1) or the presence of CTD-specific antibodies (Phase 2). A brief questionnaire has been developed to serve as a simple and practical screening tool for CTD-ILD detection. Additional research is needed to validate and evaluate the tool in longitudinal cohorts.