Relative Risk of COVID-19 Reinfection by Demographic and Vaccination Factors During the Period March 2020-October 2022.

The risk of reinfection has been difficult to quantify throughout the pandemic, making the case for COVID-19 vaccination and receipt of booster doses to the public difficult for the public health community. To address this question, Michigan statewide COVID-19 infection and vaccination data was utilized in this cross-sectional study to determine the risk of reinfection by vaccination status. Cases were divided into subgroups by vaccination status, and the risk of reinfection in the various vaccination categories was then calculated by dividing the cumulative incidence of reinfection in a vaccine category by the cumulative incidence of reinfection of those not in that category Within this population, the risk of becoming reinfected was 1.6 times higher for those who were unvaccinated than those who were vaccinated; those with a primary series saw a 27% reduced risk of reinfections compared to those without a primary series. Those with an additional booster dose had a modest improvement, with 35% reduced risk of reinfection when compared to the other groups combined. These results provide population level data to support current public health vaccination recommendations.

Formulation, Characterization and In Vitro Evaluation of Mesalamine and Bifidobacterium bifidum Loaded Hydrogel Beads in Capsule System for Colon Targeted Delivery.

Mesalamine is a first-line drug for the treatment of inflammatory bowel diseases. However, its premature release associated with marketed formulations leads to adverse effects like gastric trouble, vomiting, and diarrhoea. To minimize these side effects, colon-targeted drug delivery is essential. Besides conventional pharmacotherapy, bifidogenic probiotics with anti-inflammatory activity has been reported to elicit a significant impact on the remission of ulcerative colitis. Bifidogenic probiotics being acid-labile necessitate developing a gastro-resistant formulation for enhancing the delivery of viable cells to the colon. The present study was aimed at developing a fixed-dose unit dosage form of mucoadhesive hydrogel beads loaded with mesalamine and Bifidobacterium bifidum further encapsulated in Eudragit® capsules for the targeted drug delivery at colonic pH. The hydrogel beads were prepared by ionotropic gelation, with the effect of single and dual-crosslinking approaches on various formulation characteristics studied. Standard size 00 Eudragit® gastro-resistant capsules were prepared and the dried beads were filled inside the capsule shells. The formulation was then evaluated for various parameters, including physicochemical characterization, in vitro biocompatibility and anti-inflammatory activity. No interaction was observed between the drug and the polymers, as confirmed through FTIR, XRD, and DSC analysis. The mean particle size of the beads was ~ 457-485 µm. The optimized formulation showed a drug entrapment efficiency of 95.4 ± 2.58%. The Eudragit® capsule shells disintegrated in approximately 13 min at pH 7.4. The mucoadhesive hydrogel beads sustained the drug release above 18 h, with 50% of the drug released by the end of 12 h. The optimized formulation demonstrated significant (p < 0.05) gastro-resistance, biocompatibility, sustained drug release, cell viability, and anti-inflammatory activity.

Description of new sign of integral (∫) for rotational deformity of distal femur.

PURPOSE: Femur shaft fractures commonly occur due to high velocity trauma and most of them are fixed with nailing. Malrotation is common after fixation. A rotational malalignment more than 30° is a deformity which requires correction. Various techniques described for rotational deformities are: the 'cable techniques' for the determination of varus-valgus malalignment; the 'hyperextension test', 'radiographic recurvatum sign', 'tibial plateau sign', and 'meterstick technique' for length analysis; and the 'hip rotation test', 'lesser trochanter shape sign', 'cortical step sign', and 'diameter difference sign' for rotational analysis. We describe integration sign at the medial or lateral aspect of notch of femur in fixed internal or external rotation due to condensation of trabeculae. METHODS: This is a prospective observational study. Informed consent was taken, and this study was approved by institutional review board. C arm imaging study of 50 knees was done at our institution in which rotational profile of distal femur was analyzed In 3 different views -AP , Internal and external rotation views. The rotation views were taken sequentially and each observer was asked to identify the sign at its appearance and at rotation when it was best seen. All the observers were asked to draw the sign on linear line diagram of distal femur. The data was analysed statistically. RESULTS: Sign of integral (∫) for rotational deformity was seen at Mean external rotation of  22±1.71 with a range of 19 degree to 25 degree and  Mean internal rotation of 15.78±1.21 with a range of 14 degree to 18 degree. CONCLUSION: The integration sign can be used as intraoperative C arm sign to understand the rotational deformity of distal fragment of femur. This helps the surgeon to understand the alignment and revise if needed intraoperatively. If combined with position of lesser trochanter, this will give alignment for both proximal as well as distal fragment of femur.

Dissection of QTLs conferring drought tolerance in B. carinata derived B. juncea introgression lines.

BACKGROUND: Drought is one of the important abiotic stresses that can significantly reduce crop yields. In India, about 24% of Brassica juncea (Indian mustard) cultivation is taken up under rainfed conditions, leading to low yields due to moisture deficit stress. Hence, there is an urgent need to improve the productivity of mustard under drought conditions. In the present study, a set of 87 B. carinata-derived B. juncea introgression lines (ILs) was developed with the goal of creating drought-tolerant genotypes. METHOD: The experiment followed the augmented randomized complete block design with four blocks and three checks. ILs were evaluated for seed yield and its contributing traits under both rainfed and irrigated conditions in three different environments created by manipulating locations and years. To identify novel genes and alleles imparting drought tolerance, Quantitative Trait Loci (QTL) analysis was carried out. Genotyping-by-Sequencing (GBS) approach was used to construct the linkage map. RESULTS: The linkage map consisted of 5,165 SNP markers distributed across 18 chromosomes and spanning a distance of 1,671.87 cM. On average, there was a 3.09 cM gap between adjoining markers. A total of 29 additive QTLs were identified for drought tolerance; among these, 17 (58.6% of total QTLs detected) were contributed by B. carinata (BC 4), suggesting a greater contribution of B. carinata towards improving drought tolerance in the ILs. Out of 17 QTLs, 11 (64.7%) were located on the B genome, indicating more introgression segments on the B genome of B. juncea. Eight QTL hotspots, containing two or more QTLs, governing seed yield contributing traits, water use efficiency, and drought tolerance under moisture deficit stress conditions were identified. Seventeen candidate genes related to biotic and abiotic stresses, viz., SOS2, SOS2 like, NPR1, FAE1-KCS, HOT5, DNAJA1, NIA1, BRI1, RF21, ycf2, WRKY33, PAL, SAMS2, orf147, MAPK3, WRR1 and SUS, were reported in the genomic regions of identified QTLs. CONCLUSIONS: The significance of B. carinata in improving drought tolerance and WUE by introducing genomic segments in Indian mustard is well demonstrated. The findings also provide valuable insights into the genetic basis of drought tolerance in mustard and pave the way for the development of drought-tolerant varieties.

Universal Single-Step Approach to the Immobilization of Cyclodextrins in a Supercritical Medium for Capturing Drug, Dye, and Metal Nanoclusters.

By utilizing nanoreactor-like structures, the immobilization of macromolecules such as calixarenes and cyclodextrins (CD) with bucket-like structures provides new possibilities for engineered surface-molecule systems. The practical use of any molecular system depends on the availability of a universal procedure for immobilizing molecules with torus-like structures on various surfaces while maintaining identical operating parameters. There are currently several steps, including toxic solvent-based approaches using modified ß-CD to covalently attach to surfaces with multistep reactions. However, the existing multistep process results in molecular orientation, restricts the accessibility of the hydrophobic barrel of ß-CD's for practical use, and is effectively unable to use the surfaces immobilized with ß-CD for a variety of applications. In this study, it was demonstrated that ß-CD attached to the oxide-based semiconductor and metal surfaces through a condensation reaction between the hydroxyl-terminated oxide-based semiconductor/metal oxide and ß-CD in supercritical carbon dioxide (SCCO2) as a medium. The primary benefit of SCCO2-assisted grafting of unmodified ß-CD on various oxide-based metal and semiconductor surfaces is that it is a simple, efficient, one-step process and that it is ligand-free, scalable, substrate-independent, and uses minimal energy. Various physical microscopy and chemical spectroscopic methods were used to analyze the grafted ß-CD oligomers. The application of the grafted ß-CD films was demonstrated by the immobilization of rhodamine B (RhB), a dye, and dopamine, a drug. The in situ nucleation and growth of silver nanoclusters (AgNCs) in the molecular systems were studied for antibacterial and tribological properties by utilizing the guest-host interaction ability of ß-CD.

Interdigitated electrodes-based Au-MoS2hybrid gas sensor for sensing toxic CO and NH3gases at room temperature.

In the quest to create effective sensors that operate at room temperature, consume less power and maintain their stability over time for detecting toxic gases in the environment, molybdenum disulfide (MoS2) and MoS2-based hybrids have emerged as potent materials. In this context, the current work describes the fabrication of Au-MoS2hybrid gas sensor fabricated on gold interdigitated electrodes (GIEs) for sensing harmful CO and NH3gases at room temperature. The GIEs-based Au-MoS2hybrid sensors are fabricated by decorating MoS2nanoflowers (MNF) with varying size of Au nanoparticles using an inert gas evaporation technique. It is observed that by varying the size of Au nanoparticles, the crystallinity gets modified, as confirmed by x-ray diffraction and Micro-Raman spectroscopy (µRS). The gas sensing measurements revealed that the best sensing response is found from the Au-MoS2hybrid (with an average particle size of 10 nm). This particular hybrid shows a 79% response to CO exposure and a 69% response to NH3exposure. The measurements are about 3.5 and 5 times higher than the bare MoS2when exposed to CO and NH3at room temperature, respectively. This enhancement in sensing response is attributed to the modified interfacial interaction between the Au nanoparticles and MNF gets improved, which leads to the formation of a Schottky barrier, as confirmed using x-ray photoelectron spectroscopy and ultraviolet photoelectron spectroscopy analysis. This enables the development of efficient gas sensors that respond quickly to changes in the gas around them.

Discovery of blood-brain barrier permeable and orally bioavailable caffeine-based amide derivatives as acetylcholinesterase inhibitors.

Caffeine is one of the privileged natural products that shows numerous effects on the central nervous system. Herein, thirty-one caffeine-based amide derivatives were synthesized and evaluated in vitro for their anticholinesterase activity. The introduction of the amide group to the caffeine core augmented its anticholinesterase activity from an IC50 value of 128 to 1.32 µM (derivative, 6i). The SAR study revealed that N7 substitution on caffeine core is favorable over N1, and the presence of amide 'carbonyl' as a part of the linker contributes to the biological activity. The caffeine core of 6i exhibits interactions with the peripheral anionic site, whereas the N-benzyl ring fits nicely inside the catalytic anionic site. Analog 6i inhibits AChE in a mixed-type mode (Ki 4.58 µM) and crosses the BBB in an in-vitro PAMPA assay. Compound 6i has a descent metabolic stability in MLM (>70% remaining after 30 min) and favorable oral pharmacokinetics in Swiss albino mice.

Sustainable functionalized chitosan based nano-composites for wound dressings applications: A review.

Functionalized chitosan nanocomposites have been studied for wound dressing applications due to their excellent antibacterial and anti-fungal properties. Polysaccharides show excellent antibacterial and drug-release properties and can be utilized for wound healing. In this article, we comprise distinct approaches for chitosan functionalization, such as photosensitizers, dendrimers, graft copolymerization, quaternization, acylation, carboxyalkylation, phosphorylation, sulfation, and thiolation. The current review article has also discussed brief insights on chitosan nanoparticle processing for biomedical applications, including wound dressings. The chitosan nanoparticle preparation technologies have been discussed, focusing on wound dressings owing to their targeted and controlled drug release behavior. The future directions of chitosan research include; a) finding an effective solution for chronic wounds, which are unable to heal completely; b) providing effective wound healing solutions for diabetic wounds and venous leg ulcers; c) to better understanding the wound healing mechanism with such materials which can help provide the optimum solution for wound dressing; d) to provide an improved treatment option for wound healing.

Dynamic heterogeneity in polydisperse systems: A comparative study of the role of local structural order parameter and particle size.

In polydisperse systems, describing the structure and any structural order parameter (SOP) is not trivial as it varies with the number of species we use to describe the system, M. Depending on the degree of polydispersity, there is an optimum value of M = M0 where we show that the mutual information of the system increases. However, surprisingly, the correlation between a recently proposed SOP and the dynamics is highest for M = 1. This effect increases with polydispersity. We find that the SOP at M = 1 is coupled with the particle size, σ, and this coupling increases with polydispersity and decreases with an increase in M. Careful analysis shows that at lower polydispersities, the SOP is a good predictor of the dynamics. However, at higher polydispersity, the dynamics is strongly dependent on σ. Since the coupling between the SOP and σ is higher for M = 1, it appears to be a better predictor of the dynamics. We also study the Vibrality, an order parameter independent of structural information. Compared to SOP, at high polydispersity, we find Vibrality to be a marginally better predictor of the dynamics. However, this high predictive power of Vibrality, which is not there at lower polydispersity, appears to be due to its stronger coupling with σ. Therefore, our study suggests that for systems with high polydispersity, the correlation of any order parameter and σ will affect the correlation between the order parameter and dynamics and need not project a generic predictive power of the order parameter.

A comparative study of the correlation between the structure and the dynamics for systems interacting via attractive and repulsive potentials.

We present the study of the structure-dynamics correlation for systems interacting via attractive Lennard-Jones (LJ) and its repulsive counterpart, the Weeks-Chandler-Andersen (WCA) potentials. The structural order parameter (SOP) is related to the microscopic mean-field caging potential. At a particle level, the SOP shows a distribution. Although the two systems have similar pair structures, their average SOP differs. However, this difference alone is insufficient to explain the well known slowing down of the dynamics in the LJ system at low temperatures. The slowing down can be explained in terms of a stronger coupling between the SOP and the dynamics. To understand the origin of this system specific coupling, we study the difference in the microscopic structure between the hard and soft particles. We find that for the LJ system, the structural differences of the hard and soft particles are more significant and have a much stronger temperature dependence compared to the WCA system. Thus, the study suggests that attractive interaction creates more structurally different communities. This broader difference in the structural communities is probably responsible for stronger coupling between the structure and dynamics. Thus, the system specific structure-dynamics correlation, which also leads to a faster slowing down in the dynamics, appears to have a structural origin. A comparison of the predictive power of our SOP with the local energy and two body excess entropy in determining the dynamics shows that in the LJ system, the enthalpy plays a dominant role and in the WCA system, the entropy plays a dominant role, and our SOP can capture both these contributions.

Comprehensive analysis of microRNAs and their target genes in oral submucous fibrosis.

The objective of the study is to understand the role of experimentally validated microRNAs (miRNAs) contributing to the acquisition of oncogenic phenotype in oral submucous fibrosis (OSF) by computational analysis. A comprehensive review was carried out to corroborate and summarize altered miRNA expression in OSF by retrieving relevant publications querying MEDLINE, Web of Science, Embase, and Scopus. The association between the miRNA-mRNA was performed using miRTarBase 8.0. The visualization of the miRNA-mRNA interaction was plotted using Cytoscape. MIENTURNET was used for the pathway analysis. Enrichment analysis was carried out for elucidating the hierarchical functions of miRNAs related to the acquisition of biological processes involved in the development of cancer. Thirteen miRNAs (hsa-miR-499a, hsa-miR-200b, hsa-miR-200c, hsa-miR-1246, hsa-miR-31, hsa-miR-10b, hsa-miR-21, hsa-miR-203, hsa-miR-455, hsa-miR-760, hsa-miR-623, hsa-miR-610, and hsa-miR-509-3-5p) were found to be deregulated in OSF. A total of 371 experimentally validated genes were shown to be interacting with the OSF-associated miRNAs. The targets of antifibrotic and profibrotic miRNAs were enriched in the cancer-related pathways. Dysregulated miRNA and its target genes illustrate the physiological role of miRNAs in fibrosis. Understanding the miRNA-mediated fibrotic signaling and targetting the specific miRNA-target gene interaction might provide relevant cues to ameliorate the fibrotic disease.

Artificial Protein Cage with Unusual Geometry and Regularly Embedded Gold Nanoparticles.

Artificial protein cages have great potential in a number of areas including cargo capture and delivery and as artificial vaccines. Here, we investigate an artificial protein cage whose assembly is triggered by gold nanoparticles. Using biochemical and biophysical methods we were able to determine both the mechanical properties and the gross compositional features of the cage which, combined with mathematical models and biophysical data, allowed the structure of the cage to be predicted. The accuracy of the overall geometrical prediction was confirmed by the cryo-EM structure determined to sub-5 Å resolution. This showed the cage to be nonregular but similar to a dodecahedron, being constructed from 12 11-membered rings. Surprisingly, the structure revealed that the cage also contained a single, small gold nanoparticle at each 3-fold axis meaning that each cage acts as a synthetic framework for regular arrangement of 20 gold nanoparticles in a three-dimensional lattice.

Microtia Reconstruction: Our Strategies to Improve the Outcomes.

Introduction : Autologous costal cartilage framework placement is currently the gold standard in patients with microtia. In this article, we present the modifications developed by the author, generally following the principles established by Nagata, and discuss the technical details that have led us to achieve consistently stable and good long-term outcomes for auricular reconstruction in microtia. Materials and Methods : A retrospective review of microtia reconstruction performed from 2015 to 2021 was done. Those who underwent primary reconstruction for microtia and with a minimum follow-up of 6 months with documented photographs were included. Those who underwent secondary reconstruction for microtia and those who did not follow-up for a minimum period of 6 months were excluded. Outcomes were assessed with regard to appearance, and durability of the result. Influence of certain changes like delaying reconstruction until 15 years of age, use of nylon for framework fabrication, etc. over the outcome were assessed. Results : Of 11 ears reconstructed at less than 15 years of age, only one patient (9%) had a good long-term outcome, whereas of the 17 ears reconstructed at greater than 15 years of age, nine patients (53%) had a good long-term outcome. In our experience, infections and wire extrusions were the significant events related to severe cartilage resorption. Conclusion : In our experience, delaying the first stage to 15 years or later, using double-armed nylon sutures, and reducing the projection of the third layer of the framework in select cases have helped to improve our outcomes. Second stage of reconstruction can be avoided if patient is satisfied with the projection achieved in the first stage.

Comparison of efficacy between MBT preadjusted edgewise appliance and clear aligner therapy among class I crowding cases: A randomized controlled trial.

Background: To compare the efficacy of McLaughlin Bennett Trevisi (MBT) appliance and Clear Aligner Therapy (CAT) among nonextraction Class I crowding cases. Methods: The study sample (60 patients) was allotted into two equal groups (30 patients each) using block randomization wherein Group 1: treated with 0.018" MBT appliance and Group 2: treated with CAT for correction of malocclusion. At the end of treatment (T1), treatment duration, chairside time, laboratory time, number, and type of appointments were noted from treatment record cards. For comparing the acceptability among patients treated with both modalities at T1, the patients were interviewed regarding the comfort and ease of using an appliance with a questionnaire-based survey. Results: The median number of nonscheduled/emergency and finishing stage appointments was significantly higher in Group 1 compared to Group 2 (P-value <0.001). The median duration of treatment at the scheduled, finishing, and overall appointments, was significantly higher in Group 1 compared to Group 2 (P-value <0.001). The median chairside time of all appointments was significantly higher in Group 1 compared to Group 2 (P-value <0.001). The experience with treatment and overall acceptability was significantly higher in Group 2 compared to Group 1 (P-value <0.001). However, mean laboratory time per aligner fabrication in Group 2 was 30.26 ± 3.45 min against no laboratory time consumed in Group 1. Conclusions: CAT significantly reduces treatment duration, chairside time, number of nonscheduled/emergency, and finishing stage appointments in nonextraction Class I crowding cases. Prospective studies with 3D aligner systems are recommended to add further evidence in this regard. Clinical Trials Registry-India Registration No: CTRI/2018/04/013301.

Analysis and Interpretation of metagenomics data: an approach.

Advances in next-generation sequencing technologies have accelerated the momentum of metagenomic studies, which is increasing yearly. The metagenomics field is one of the versatile applications in microbiology, where any interaction in the environment involving microorganisms can be the topic of study. Due to this versatility, the number of applications of this omics technology reached its horizons. Agriculture is a crucial sector involving crop plants and microorganisms interacting together. Hence, studying these interactions through the lenses of metagenomics would completely disclose a new meaning to crop health and development. The rhizosphere is an essential reservoir of the microbial community for agricultural soil. Hence, we focus on the R&D of metagenomic studies on the rhizosphere of crops such as rice, wheat, legumes, chickpea, and sorghum. These recent developments are impossible without the continuous advancement seen in the next-generation sequencing platforms; thus, a brief introduction and analysis of the available sequencing platforms are presented here to have a clear picture of the workflow. Concluding the topic is the discussion about different pipelines applied to analyze data produced by sequencing techniques and have a significant role in interpreting the outcome of a particular experiment. A plethora of different software and tools are incorporated in the automated pipelines or individually available to perform manual metagenomic analysis. Here we describe 8-10 advanced, efficient pipelines used for analysis that explain their respective workflows to simplify the whole analysis process.

Enhanced interfacial charge transfer on strain-induced 2D-1D/MoS2-TiO2heterostructures for electrochemical and photocatalytic applications.

Two-dimensional (2D)/one dimensionsal (1D)-MoS2/TiO2heterostructures have proven to be potent for photocatalytic applications. Enhancement of a heterostructure's photocatalytic activity may be influenced by the accumulation of strain at the interface, which affects the interfacial interaction. Keeping this in mind, the present paper reports strain-accumulated interfacial modification of 2D/1D-MoS2/TiO2heterostructures for the enhancement of photocatalytic activity. Two different synthesis methods, namely the hydrothermal and chemical vapor deposition (CVD) methods, are used for the growth of MoS2on TiO2nanostructures. Micro-Raman spectroscopy reveals that strain is accumulated at the interface of the growth of the MoS2over the TiO2nanostructures. It is further revealed that the MoS2/TiO2heterostructure synthesized by the CVD method induces compressive strain. Also, the heterostructure synthesized by the hydrothermal method induces tensile strain that modifies the charge separation at the interface, which is further confirmed by x-ray photoelectron spectroscopy (XPS). Moreover, ultraviolet photoelectron spectroscopy (UPS) reveals upward band-bending in the MoS2/TiO2heterostructure synthesized by the hydrothermal method. Similarly, the heterostructure synthesized by the CVD method shows downward band-bending that leads to improved charge separation at the interface. The modified interfaces of the heterostructures are further studied for electrochemical measurements using cyclic voltammetry (CV) and photocatalytic activity by degradation of a model compound.

Taxonomies for synthesizing the evidence on communicating numbers in health: Goals, format, and structure.

Many people, especially those with low numeracy, are known to have difficulty interpreting and applying quantitative information to health decisions. These difficulties have resulted in a rich body of research about better ways to communicate numbers. Synthesizing this body of research into evidence-based guidance, however, is complicated by inconsistencies in research terminology and researcher goals. In this article, we introduce three taxonomies intended to systematize terminology in the literature, derived from an ongoing systematic literature review. The first taxonomy provides a systematic nomenclature for the outcome measures assessed in the studies, including perceptions, decisions, and actions. The second taxonomy is a nomenclature for the data formats assessed, including numbers (and different formats for numbers) and graphics. The third taxonomy describes the quantitative concepts being conveyed, from the simplest (a single value at a single point in time) to more complex ones (including a risk-benefit trade-off and a trend over time). Finally, we demonstrate how these three taxonomies can be used to resolve ambiguities and apparent contradictions in the literature.

Blood-brain barrier permeable benzylpiperidin-4-yl-linked benzylamino benzamides as dual cholinesterase inhibitors.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder involving various pathological events. The existing options for managing the disease utterly rely on cholinesterase (ChE) inhibitors. In recent years, the dual inhibition of ChEs as a potential AD therapeutics has substantially attracted the attention of medicinal chemists. Recently, we reported benzyl piperidinyl-linked methoxy-naphthamides as dual ChE inhibitors. Herein, we investigated the peripheral anionic binding site-binding methoxy-naphthamide fragment that yielded benzyl piperidinyl-linked benzyl aminobenzamide as another class of dual ChE inhibitors. The 3,5-dimethoxy benzyl aminobenzamide, 8c1, exhibits inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with half-maximal inhibitory concentration values of 0.61 and 2.04 µM, respectively. The enzyme kinetics and molecular modeling study indicated the noncompetitive and mixed-type mode of inhibition for AChE and BChE with ki values of 0.14 and 0.46 µM, respectively. The derivative 8c1 crosses the blood-brain barrier as indicated by the Pe value of 14.34 × 10-6 cm/s in the parallel artificial membrane permeability assay. Besides this, it also inhibits the self-aggregation of amyloid-ß. The results presented herein indicate the potential of benzamide 8c1 for further investigation in preclinical models of AD.

Design, synthesis, and structure-activity relationship of caffeine-based triazoles as dual AChE and BACE-1 inhibitors.

Natural products have significantly contributed to drug discovery for neurodegenerative diseases. Caffeine is one of the well-known central nervous system(CNS)-active natural products. Besides its CNS stimulant properties, it is a mild inhibitor of acetylcholinesterase (AChE) and possesses memory-enhancing properties. The present work aimed to improve the AChE inhibition activity of the caffeine. The rationally designed caffeine-based triazoles were synthesized and evaluated in vitro for cholinesterase and ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitory activities. The attachment of triazole to the caffeine enhances its AChE inhibition activity from half-maximal inhibitory concentration (IC50 ) of 129 µM to 0.49 µM (derivative, 6l). The caffeine core interacts with the peripheral anionic site, whereas the benzyl triazole occupies the catalytic anionic site located at the bottom of the active site gorge. The structure-activity relationship revealed that the four-atom ester linker is superior to shorter linkers for connecting the caffeine core to the triazole. The 2,6-difluorobenzyl triazole-linked caffeine derivative, 6d, exhibits dual inhibition of AChE and BACE-1 with IC50 values of 1.43 and 10.9 µM, respectively. The derivative 6d inhibits AChE via a mixed-type mode with an inhibition rate constant (Ki ) value of 2.35 µM, which was corroborated by docking studies. The triazole 6d has an acceptable stability profile in human liver microsomes (t1/2 = 54 min) and was found to possess CNS permeability when evaluated using the parallel artificial membrane permeability blood-brain barrier assay. The results presented herein warrant investigating caffeine-based triazoles in preclinical models of Alzheimer's disease.

Promoting gender equality across the sustainable development goals.

Gender issues, and gender equality in particular, can be regarded as cross-cutting issues in the implementation of the Sustainable Development Goals (SDGs), even though it is unclear how they are taken into account. This study addresses this information gap by performing an assessment of the emphasis on gender issues across all the other 16 SDGs, in addition to SDG5, through a literature review and case study analysis, the basis for the newly developed framework, highlighting specific actions associated to each SDG. The 13 countries addressed in the 16 case studies include China, India, or Australia and illustrate the inclusion of SDG5 into the SDGs. Using an SDG matrix, the SDG targets are analysed. Those where an emphasis on gender equality is important in allowing them to be achieved are listed. The novelty of our approach resides in offering an in-depth analysis of how gender issues interact with the other SDGs, proposing a new analysis framework clearly identifying SDGs 1, 4, 11, 12, 14 and 16 demanding further attention for successful SD gender implementation and illustrating specific areas where further actions may be necessary, which may be used by policy-makers, raising further awareness on gender equality contribution to achieve the SDGs. A set of recommendations aimed at placing gender matters more centrally in the SDGs delivery are presented as a final contribution. These focus on the need for greater awareness and attention to good practices, to achieve successful implementation initiatives. Supplementary Information: The online version contains supplementary material available at 10.1007/s10668-022-02656-1.