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DNA is commonly known as the "molecule of life" because it holds the genetic instructions for all living organisms on Earth. The utilization of modified nucleosides holds the potential to transform the management of a wide range of human illnesses. Modified nucleosides and their role directly led to the 2023 Nobel prize. Acyclic nucleosides, due to their distinctive physiochemical and biological characteristics, rank among the most adaptable modified nucleosides in the field of medicinal chemistry. Acyclic nucleosides are more resistant to chemical and biological deterioration, and their adaptable acyclic structure makes it possible for them to interact with various enzymes. A phosphonate group, which is linked via an aliphatic functionality to a purine or a pyrimidine base, distinguishes acyclic nucleoside phosphonates (ANPs) from other nucleotide analogs. Acyclic nucleosides and their derivatives have demonstrated various biological activities such as anti-viral, anti-bacterial, anti-cancer, anti-microbial, etc. Ganciclovir, Famciclovir, and Penciclovir are the acyclic nucleoside-based drugs approved by FDA for the treatment of various diseases. Thus, acyclic nucleosides are extremely useful for generating a variety of unique bioactive chemicals. Their biological activities as well as selectivity is significantly influenced by the stereochemistry of the acyclic nucleosides because chiral acyclic nucleosides have drawn a lot of interest due to their intriguing biological functions and potential as medicines. For example, tenofovir's (R) enantiomer is roughly 50 times more potent against HIV than its (S) counterpart. We can confidently state, "The most promising developments are yet to come in the realm of acyclic nucleosides!" Herein, we have covered the most current developments in the field of chemical synthesis and therapeutic applications of acyclic nucleosides based upon our continued interest and activity in this field since mid-1990's., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The palladium-catalysed regioselective C-H chalcogenation of benzoxazines with disulfides and diselenides in air has been described. In this protocol, palladium acetate serves as the catalyst in conjunction with copper as an oxidizing agent. Through this approach, a wide array of sulfenylation and selenylation reactions of benzomorpholines have been effected, yielding results ranging from good to excellent. Thus, the established procedure demonstrates superb regioselectivity and a strong tolerance towards various functional groups and is suitable for gram-scale synthesis. Additionally, this synthetic approach offers a practical and convenient pathway for late-stage functionalization leading to the Rosenmund-von Braun reaction.

Introduction: Antibiotic resistance presents a significant global health threat to modern medicine. The awareness and attitude of future doctors undergoing training may play a crucial role in addressing this important issue, influencing the control of resistance and promoting responsible antibiotic stewardship. This study aimed to estimate knowledge, attitudes, and practices regarding antibiotic usage and antimicrobial resistance among tertiary care teaching hospital medical interns., Methodology: The questionnaire-based cross-sectional study was conducted on 123 MBBS interns from multiple medical institutions. Intern's knowledge, attitudes, and self-reported practices regarding antibiotic use were recorded., Results: Based on survey responses from 123 participants, 116 (94.31%) were aware of the adverse effects of indiscriminate antibiotic use, recognizing the risks of ineffective treatment, increased adverse effects, prolonged illness, bacterial resistance, and higher medical costs. Most (106, 86.18%) acknowledged the challenges of treating antibiotic-resistant infections, and 69 (56.10%) correctly identified that bacteria are not a cause of the common cold and flu. Most (115, 93.5%) recognized antibiotic resistance as a significant global health problem. In attitude, 90 (73%) believed antibiotics should be avoided for colds, but 80 (65%) thought they hastened fever recovery. Only 48 (39%) recognized that antibiotics contribute to resistance, while 102 (83%) agreed skipping doses fosters resistance. Most support hospital policies (118, 96%) and curriculum courses (112, 91%) for rational antibiotic use. Regarding practice, 12 (9.76%) interns admitted to overusing antibiotics, 68 (55.28%) consulted a doctor before starting antibiotics, and 87 (70.73%) checked expiry dates. Additionally, 62 (50.41%) preferred antibiotics for cough and sore throat symptoms., Conclusions: The study highlights that while interns have a good knowledge and awareness of the harms of antibiotic misuse, they are not translating this knowledge into practice. This indicates a disconnect between understanding and application. Therefore, there is a need to add a rational antibiotic prescription and stewardship module to the medical curriculum to ensure that knowledge is effectively translated into changing beliefs and practices., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee for Human Research issued approval MAMC/IEC/2023/79, dated November 22, 2023. The study was carried out from December 2023 to March 2024 after obtaining approval from the Scientific Research Committee and the Institutional Ethics Committee for Human Research (MAMC/IEC/2023/79, dated November 22, 2023. Written informed consent was obtained from each participant. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bano et al.)

A straightforward and efficient methodology has been employed for the synthesis of a diverse set of base-modified fluorescent nucleoside conjugates via Cu(I)-catalysed cycloaddition reaction of 5-ethynyl-2',3',5'-tri- O -acetyluridine/3',5'-di- O -acetyl-2'-deoxyuridine with 4-(azidomethyl)- N 9 -(4'-aryl)-9,10-dihydro-2 H ,8 H -chromeno[8,7- e ][1,3]oxazin-2-ones in t BuOH to afford the desired 1,2,3-triazoles in 92-95% yields. Treatment with NaOMe/MeOH resulted in the final deprotected nucleoside analogues. The synthesized 1,2,3-triazoles demonstrated a significant emission spectrum, featuring two robust bands in the region from 350-500 nm (with excitation at 300 nm) in fluorescence studies. Photophysical investigations revealed a dual-emissive band with high fluorescence intensity, excellent Stokes shift (140-164 nm) and superior quantum yields (0.068-0.350). Furthermore, the electronic structures of the synthesized triazoles have been further verified by DFT studies. Structural characterization of all synthesized compounds was carried out using various analytical techniques, including IR, 1 H-NMR, 13 C-NMR, 1 H- 1 H COSY, 1 H- 13 C HETCOR experiments, and HRMS measurements. The dual-emissive nature of these nucleosides would be a significant contribution to nucleoside chemistry as there are limited literature reports on the same.

A neonate presented with abdominal distension and decreased urinary output. X-ray revealed dual abdominal fluid condition-ascites with a distended bladder, along with vertebral anomalies. The possibility of urinary ascites and neurogenic bladder was kept, which was further confirmed on evaluation. Here, we emphasise the crucial role of abdominal X-ray as a diagnostic tool in uncovering this intricate medical puzzle. By detailing the clinical presentation, diagnostic approach and treatment strategy, the report contributes insights into the rare and complex abdominal condition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Chromones are well known as fundamental structural elements found in numerous natural compounds and medicinal substances. The Schiff bases of chromones have a much wider range of pharmacological applications such as antitumor, antioxidant, anti-HIV, antifungal, anti-inflammatory, and antimicrobial properties. A lot of research has been carried out on chromone-based copper(ii) Schiff-base complexes owing to their role in the organometallic domain and promise as potential bioactive cores. This review article is centered on copper(ii) Schiff-base complexes derived from chromones, highlighting their diverse range of pharmacological applications documented in the past decade, as well as the future research opportunities they offer., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Umbilical cord milking (UCM) and delayed cord clamping (DCC) are strategies that improve the hemodynamic condition of the newborn and also increase the storage of iron. This study aimed to compare the effects of DCC with or without milking in late preterm and term neonates at different time intervals after birth (60, 120, and 180 seconds) on hematological and hemodynamic parameters in neonates at six weeks of age., Materials and Methods: In this double-arm, parallel-group, triple-blind, and active-controlled trial, all 150 eligible neonates were randomized with allocation concealment into three groups: Group A (DCC with UCM at 60 seconds), Group B (DCC with UCM at 120 seconds), and Group C (only DCC for 180 seconds). Hemodynamic parameters were recorded and compared during the first 48 hours, and hematological parameters were compared at six weeks of age., Results: At six weeks, a significant difference in hemoglobin levels was noted between Groups A, B, and C (p<0.001). The difference in serum ferritin values at six weeks was also statistically significant in comparisons across all three groups (p=0.003). Regarding secondary outcomes examined, hemodynamic parameters and the incidence of neonatal hyperbilirubinemia were found to be comparable at 48 hours after birth., Conclusion: DCC followed by UCM at 120 seconds and DCC till 180 seconds proves superior to DCC with UCM at 60 seconds in preserving elevated hemoglobin levels and iron stores in neonates at six weeks of age. DCC for 180 seconds yielded comparable results, followed by UCM at 120 seconds. All three methods are considered safe and effective without compromising the neonate's hemodynamics., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Singh et al.)

Iodine-containing molecules, especially hypervalent iodine compounds, have gained significant attention in organic synthesis. They are valuable and sustainable reagents, leading to a remarkable surge in their use for chemical transformations. One such hypervalent iodine compound, phenyliodine bis(trifluoroacetate)/bis(trifluoroacetoxy)iodobenzene, commonly referred to as PIFA, has emerged as a prominent candidate due to its attributes of facile manipulation, moderate reactivity, low toxicity, and ready availability. PIFA presents an auspicious prospect as a substitute for costly organometallic catalysts and environmentally hazardous oxidants containing heavy metals. PIFA exhibits remarkable catalytic activity, facilitating an array of consequential organic reactions, including sulfenylation, alkylarylation, oxidative coupling, cascade reactions, amination, amidation, ring-rearrangement, carboxylation, and numerous others. Over the past decade, the application of PIFA in synthetic chemistry has witnessed substantial growth, necessitating an updated exploration of this field. In this discourse, we present a concise overview of PIFA's applications as a 'green' reagent in the domain of synthetic organic chemistry. A primary objective of this article is to bring to the forefront the scientific community's awareness of the merits associated with adopting PIFA as an environmentally conscientious alternative to heavy metals.

Pyrimidine is a pharmacologically important moiety that exhibits diverse biological activities. This review reflects the growing significance of transition metal-catalyzed reactions for the synthesis of pyrimidines (with no discussion being made on the transition metal-catalyzed functionalization of pyrimidines). The effect of different catalysts on the selectivity/yields of pyrimidines and catalyst recyclability (wherever applicable) are described, together with attempts to illustrate the role of the catalyst through mechanisms. Although several methods have been researched for synthesizing this privileged scaffold, there has been a considerable push to expand transition metal-catalyzed, sustainable, efficient and selective synthetic strategies leading to pyrimidines. The aim of the authors with this update (2017-2023) is to drive the designing of new transition metal-mediated protocols for pyrimidine synthesis., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Thiazolines and their derivatives hold significant importance in the field of medicinal chemistry due to their promising potential as pharmaceutical agents. These molecular entities serve as critical scaffolds within numerous natural products, including curacin A, thiangazole, and mirabazole, and play a vital role in a wide array of physiological reactions. Their pharmacological versatility encompasses anti-HIV, neurological, anti-cancer, and antibiotic activities. Over the course of recent decades, researchers have extensively explored and developed analogs of these compounds, uncovering compelling therapeutic properties such as antioxidant, anti-tumor, anti-microbial, and anti-inflammatory effects. Consequently, thiazoline-based compounds have emerged as noteworthy targets for synthetic endeavors. In this review, we provide a comprehensive summary of recent advancements in the synthesis of thiazolines and thiazoline-based derivatives, along with an exploration of their diverse potential applications across various scientific domains., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We report herein an efficient visible-light-promoted approach for the regioselective decarboxylative C-H acylation of N -methyl-3-phenylquinoxalin-2(1 H )-ones using α-oxo-2-phenylacetic acids via dual palladium-photoredox catalysis. The reactions were carried out at room temperature in the presence of 24 W blue LEDs. The established protocol tolerated a wide range of functional groups and enabled the synthesis of several acylated N -methyl-3-phenylquinoxalin-2(1 H )-ones in good to excellent yields. The proposed mechanism for this transformation was supported by control experiments., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Globally, human papillomavirus (HPV) infection is the leading cause of mortality associated with cervical cancer, oral cancer (oropharyngeal), and head and neck squamous cell carcinoma (HNSCC). It is essential to explore anti-cancer drugs against life-threatening HPV infections. Aiming to search for potentially better anticancer agents, a small library of β- C -glycosylated methylidene succinimides have been synthesized under bulk and mechanical grinding conditions using the Wittig olefination reaction. Thus, the reaction of different 2,3,4,6-tetra- O -benzyl- C -glycosyl aldehydes with N -aryl/alkyl maleimides in the presence of PPh 3 at 25 °C under bulk and mechanical grinding conditions results in the formation of stereochemically defined ( E )-3-(2,3,4,6-tetra- O -benzyl- C -glycosylmethylidene)- N -alkyl/phenyl succinimides, which upon debenzylation with 1 M BCl 3 in DCM at -78 °C lead to the synthesis of ( E )-3-( C -glycosylmethylidene)- N -alkyl/phenyl succinimides in good to excellent yields. The developed methodology is efficient and environmentally benign because there is no use of organic solvents, and the products are obtained in a stereochemically defined form and in high yields. The aqueous solubility of all synthesized β- C -glycosylated methylidene succinimides makes them potential candidates for the evaluation of their different biological activities. In the present work, the synthesized glycosylated alkylidine succinimides were subjected to an in-silico molecular docking study against the E6 oncoprotein of high-risk type HPV16, which is responsible for the inactivation of the tumor suppressor p53 protein. Analysis of the molecular docking data revealed that the synthesized compounds are effective inhibitors of HPV infection, which is the cause of oral, head and neck, and cervical cancer. In comparison with the positive control 5-FU, an anti-cancer drug used in chemotherapy, more than fifteen compounds were found to be better E6 protein inhibitors.

A solvent catalysed and metal catalyst-free Groebke-Blackburn-Bienayame three component reaction (GBB-3CR) has been developed for the synthesis of 2-(β-D-glycal-1-yl)-3-N-alkylamino-1-azaindolizines and 2-alkyl/aryl/heteroaryl-3-N-alkylamino-1-azaindolizines. The modified GBB reaction protocol is highly efficient, versatile, atom economic and has been performed in hexafluoroisopropanol (HFIP) without any added catalyst. The GBB-3CR showed high tolerance for a large no of substrates in term of aldehydes, differently substituted 2-aminopyridines and isocyanides without being affected by the presence of electron donating and electron withdrawing substituents at either aldehydes or 2-aminopyridines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A highly stereoselective, efficient and facile route was achieved for the synthesis of novel and biochemically potent sugar fused pyrano[3,2- c ]pyranone derivatives starting from inexpensive, naturally occurring d-galactose and d-glucose. First, β- C -glycopyranosyl aldehydes were synthesized from these d-hexose sugars in six steps, with overall yields 41-55%. Next, two different 1- C -formyl glycals were synthesized from these β- C -glycopyranosyl aldehydes by treatment in basic conditions. The optimization of reaction conditions was carried out following reactions between 1- C -formyl galactal and 4-hydroxycoumarin. Next, 1- C -formyl galactal and 1- C -formyl glucal were treated with nine substituted 4-hydroxy coumarins at room temperature (25 °C) in ethyl acetate for ∼1-2 h in the presence of l-proline to obtain exclusively single diastereomers of pyrano[3,2- c ]pyranone derivatives in excellent yields. Four compounds were found to be active for the MCF-7 cancer cell line. The MTT assay, apoptosis assay and migration analysis showed significant death of the cancer cells induced by the synthesized compounds., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Naturally occurring coumarin and sugar molecules have a diverse range of applications along with superior biocompatibility. Coumarin, a member of the benzopyrone family, exhibits a wide spectrum of medicinal properties, such as anti-coagulant, anti-bacterial, anti-tumor, anti-oxidant, anti-cancer, anti-inflammatory and anti-viral activities. The sugar moiety functions as the central scaffold for the synthesis of complex molecules, attributing to their excellent biocompatibility, well-defined stereochemistry, benign nature and outstanding aqueous solubility. When the coumarin moiety is conjugated with the sugar or nucleoside molecule, the resulting conjugates exhibit significant biological properties. Due to the remarkable growth of such bioconjugates in the field of science over the last decade, owing to their future prospect as a potential bioactive core, an update to this area is very much needed. The present review focusses on the synthesis, characterization and the various therapeutic applications of coumarin conjugates, i.e., sugar and nucleoside coumarin conjugates along with their perspective for future research., Competing Interests: Declaration of competing interest All authors have no conflict of interest with this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A rhodium-catalysed, regioselective synthetic methodology for selenylation and sulfenylation of 3-phenyl quinoxolinones has been developed through N-directed C-H activation in the presence of silver triflimide, and silver carbonate using dichalcogenides 'on water'. The methodology has been proven to be efficient, regioselective and green. Using this method, a range of selenylations and sulfenylations of the substrates has been carried out in good to excellent yields. Further, late-stage functionalisation produced potential anti-tumour, anti-fungal and anti-bacterial agents making these compounds potential drug candidates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A microwave assisted, palladium-catalyzed regioselective halogenation of 3-phenyl-2 H -benzo[ b ][1,4]oxazin-2-ones has been demonstrated using inexpensive and readily available N -halosuccinimide. The reaction utilizes the nitrogen atom present in the heterocyclic ring as the directing group to afford regioselective halogenated products in good to moderate yields. The established protocol provides wide substrate scope, high functional group tolerance, and high atom and step economy. The reaction proved to be cost-effective and time-saving as it required only a few minutes for completion and is amenable to gram scale. The halogen atoms present in synthesized products provide further scope for post-functionalization. Several post-functionalized products have also been synthesised to demonstrate the high utility of the reaction in the field of drug discovery and late-stage functionalization., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A sustainable and environment-friendly approach for the regioselective acylation of 1-methyl-3-phenyl quinoxaline-2(1 H )-ones has been developed in water. The present protocol requires palladium acetate as a catalyst and exhibits a wide substrate scope by employing commercially available, non-toxic aldehydes, benzyl alcohols and toluenes as acyl surrogates. The mechanistic studies demonstrated the adoption of a free radical pathway for this transformation. Furthermore, the established protocol exhibits excellent regioselectivity and high functional group tolerance and is amenable to the gram scale. The established synthetic method also provides a practical and convenient route for the late-stage functionalization of some potential drug candidates.

As of 2 September 2021, United States nursing homes have reported >675,000 COVID-19 cases and >134,000 deaths according to the Centers for Medicare & Medicaid Services (CMS). More than 205,000,000 persons in the United States had received at least one dose of a COVID-19 vaccine (62% of total population) as of 2 September 2021. We investigate the role of vaccination in controlling future COVID-19 outbreaks. We developed a stochastic, compartmental model of SARS-CoV-2 transmission in a 100-bed nursing home with a staff of 99 healthcare personnel (HCP) in a community of 20,000 people. We parameterized admission and discharge of residents in the model with CMS data, for a within-facility basic reproduction number (R 0 ) of 3.5 and a community R 0 of 2.5. The model also included: importation of COVID-19 from the community, isolation of SARS-CoV-2 positive residents, facility-wide adherence to personal protective equipment (PPE) use by HCP, and testing. We systematically varied coverage of mRNA vaccine among residents, HCP, and the community. Simulations were run for 6 months after the second dose in the facility, with results summarized over 1,000 simulations. Expected resident cases decreased as community vaccination increased, with large reductions at high HCP coverage. The probability of a COVID-19 outbreak was lower as well: at HCP vaccination coverage of 60%, probability of an outbreak was below 20% for community coverage of 50% or above. At high coverage, stopping asymptomatic screening and facility-wide testing yielded similar results. Results suggest that high coverage among HCP and in the community can prevent infections in residents. When vaccination is high in nursing homes, but not in their surrounding communities, asymptomatic and facility-wide testing remains necessary to prevent the spread of COVID-19. High adherence to PPE may increase the likelihood of containing future COVID-19 outbreaks if they occur., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Mathematical modeling of healthcare-associated infections and multidrug-resistant organisms improves our understanding of pathogen transmission dynamics and provides a framework for evaluating prevention strategies. One way of improving the communication among modelers is by providing a standardized way of describing and reporting models, thereby instilling confidence in the reproducibility and generalizability of such models. We updated the Overview, Design concepts, and Details protocol developed by Grimm et al [11] for describing agent-based models (ABMs) to better align with elements commonly included in healthcare-related ABMs. The Modeling Infectious Diseases in Healthcare Network (MInD-Healthcare) framework includes the following 9 key elements: (1) Purpose and scope; (2) Entities, state variables, and scales; (3) Initialization; (4) Process overview and scheduling; (5) Input data; (6) Agent interactions and organism transmission; (7) Stochasticity; (8) Submodels; and (9) Model verification, calibration, and validation. Our objective is that this framework will improve the quality of evidence generated utilizing these models., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

The coronavirus disease-2019 (COVID-19) pandemic has had a significant impact on patients with underlying malignancy. In this article, we summarize emerging data related to patients with cancer and COVID-19. Among patients with COVID-19, a higher proportion have an underlying diagnosis of cancer than seen in the general population. Also, patients with malignancy are likely to be more vulnerable than the general population to contracting COVID-19. Mortality is significantly higher in patients with both cancer and COVID-19 compared with the overall COVID-19-positive population. The early months of the pandemic saw a decrease in cancer screening and diagnosis, as well as postponement of standard treatments, which could lead to excess deaths from cancer in the future.

From the viewpoint of meeting the current green chemistry challenges in chemical synthesis, there is a need to disseminate how the cocktail of acylation and activation can play a pivotal role in affording bioactive acylated products comprising substituted ketone motifs in fewer reaction steps, with higher atom-economy and improved selectivity. In recent years, a significant number of articles employing the title compounds "aldehydes" as magnificent acylation surrogates which are less toxic and widely applicable have been published. This review sheds light on the compounds use for selective acylation of arene, heteroarene and alkyl (sp3, sp2 and sp) C-H bonds by proficient utilization of the C-H activation strategy. Critical insights into selective acylation of diverse moieties for the synthesis of bioactive compounds are presented in this review that will enable academic and industrial researchers to understand the mechanistic aspects involved and fruitfully employ these strategies in designing novel molecules.

Although there is increasing importance placed on the use of mathematical models for the effective design and management of long-term parasite elimination, it is becoming clear that transmission models are most useful when they reflect the processes pertaining to local infection dynamics as opposed to generalized dynamics. Such localized models must also be developed even when the data required for characterizing local transmission processes are limited or incomplete, as is often the case for neglected tropical diseases, including the disease system studied in this work, viz. lymphatic filariasis (LF). Here, we draw on progress made in the field of computational knowledge discovery to present a reconstructive simulation framework that addresses these challenges by facilitating the discovery of both data and models concurrently in areas where we have insufficient observational data. Using available data from eight sites from Nigeria and elsewhere, we demonstrate that our data-model discovery system is able to estimate local transmission models and missing pre-control infection information using generalized knowledge of filarial transmission dynamics, monitoring survey data, and details of historical interventions. Forecasts of the impacts of interventions carried out in each site made by the models estimated using the reconstructed baseline data matched temporal infection observations and provided useful information regarding when transmission interruption is likely to have occurred. Assessments of elimination and resurgence probabilities based on the models also suggest a protective effect of vector control against the reemergence of LF transmission after stopping drug treatments. The reconstructive computational framework for model and data discovery developed here highlights how coupling models with available data can generate new knowledge about complex, data-limited systems, and support the effective management of disease programs in the face of critical data gaps., Competing Interests: The authors have declared that no competing interests exist.

Concern is emerging regarding the challenges posed by spatial complexity for modelling and managing the area-wide elimination of parasitic infections. While this has led to calls for applying heterogeneity-based approaches for addressing this complexity, questions related to spatial scale, the discovery of locally-relevant models, and its interaction with options for interrupting parasite transmission remain to be resolved. We used a data-driven modelling framework applied to infection data gathered from different monitoring sites to investigate these questions in the context of understanding the transmission dynamics and efforts to eliminate Simulium neavei- transmitted onchocerciasis, a macroparasitic disease that causes river blindness in Western Uganda and other regions of Africa. We demonstrate that our Bayesian-based data-model assimilation technique is able to discover onchocerciasis models that reflect local transmission conditions reliably. Key management variables such as infection breakpoints and required durations of drug interventions for achieving elimination varied spatially due to site-specific parameter constraining; however, this spatial effect was found to operate at the larger focus level, although intriguingly including vector control overcame this variability. These results show that data-driven modelling based on spatial datasets and model-data fusing methodologies will be critical to identifying both the scale-dependent models and heterogeneity-based options required for supporting the successful elimination of S. neavei-borne onchocerciasis.

The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo. All of the compounds tested had an inhibitory effect on the blood stage of P. falciparum at submicromolar concentrations, with the best showing 50% inhibitory concentrations (IC 50 ) of around 500 nM against drug-resistant P. falciparum parasites. These compounds showed inhibitory actions against plasmepsins, a family of malarial aspartyl proteases, and exhibited a marked killing effect on blood stage Plasmodium. In chloroquine-resistant Plasmodium berghei and P. berghei ANKA infected mouse models, treating mice with both compounds led to a significant decrease in blood parasite load. Importantly, two of the compounds displayed an inhibitory effect on the gametocyte stages (III-V) of P. falciparum in culture and the liver-stage infection of P. berghei both in in vitro and in vivo. Altogether, our findings suggest that fast-acting hydroxyethylamine-phthalimide analogs targeting multiple life stages of the parasite could be a valuable chemical lead for the development of novel antimalarial drugs.

Botulinum neurotoxins (BoNTs), the most poisonous proteins known to humankind, are a family of seven (serotype A to G) immunologically distinct proteins synthesized primarily by different strains of the anaerobic bacterium Clostridium botulinum Being the causative agents of botulism, the toxins block neurotransmitter release by specifically cleaving one of the three soluble N -ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, thereby inducing flaccid paralysis. The development of countermeasures and therapeutics against BoNTs is a high-priority research area for public health because of their extreme toxicity and potential for use as biowarfare agents. Extensive research has focused on designing antagonists that block the catalytic activity of BoNTs. In this study, we screened 300 small natural compounds and their analogues extracted from Indian plants for their activity against BoNT serotype A (BoNT/A) as well as its light chain (LCA) using biochemical and cellular assays. One natural compound, a nitrophenyl psoralen (NPP), was identified to be a specific inhibitor of LCA with an in vitro 50% inhibitory concentration (IC 50 ) value of 4.74 ± 0.03 µM. NPP was able to rescue endogenous synaptosome-associated protein 25 (SNAP-25) from cleavage by BoNT/A in human neuroblastoma cells with an IC 50 of 12.2 ± 1.7 µM, as well as to prolong the time to the blocking of neutrally elicited twitch tensions in isolated mouse phrenic nerve-hemidiaphragm preparations. IMPORTANCE The long-lasting endopeptidase activity of BoNT is a critical biological activity inside the nerve cell, as it prompts proteolysis of the SNARE proteins, involved in the exocytosis of the neurotransmitter acetylcholine. Thus, the BoNT endopeptidase activity is an appropriate clinical target for designing new small-molecule antidotes against BoNT with the potential to reverse the paralysis syndrome of botulism. In principle, small-molecule inhibitors (SMIs) can gain entry into BoNT-intoxicated cells if they have a suitable octanol-water partition coefficient (log P ) value and other favorable characteristics (P. Leeson, Nature 481:455-456, 2012, https://doi.org/10.1038/481455a). Several efforts have been made in the past to develop SMIs, but inhibitors effective under in vitro conditions have not in general been effective in vivo or in cellular models (L. M. Eubanks, M. S. Hixon, W. Jin, S. Hong, et al., Proc Natl Acad Sci U S A 104:2602-2607, 2007, https://doi.org/10.1073/pnas.0611213104). The difference between the in vitro and cellular efficacy presumably results from difficulties experienced by the compounds in crossing the cell membrane, in conjunction with poor bioavailability and high cytotoxicity. The screened nitrophenyl psoralen (NPP) effectively antagonized BoNT/A in both in vitro and ex vivo assays. Importantly, NPP inhibited the BoNT/A light chain but not other general zinc endopeptidases, such as thermolysin, suggesting high selectivity for its target. Small-molecule (nonpeptidic) inhibitors have better oral bioavailability, better stability, and better tissue and cell permeation than antitoxins or peptide inhibitors., (Copyright © 2018 American Society for Microbiology.)

Background: Coumarin derivatives possess a wide range of biological activities. By functionalization of the parent coumarin skeleton that has neither antioxidant nor biological activity, a series of new bio-antioxidants has been designed., Results: New antioxidant compositions (equimolar binary and ternary mixtures) of eight 4-methylcoumarins and three related compounds have been tested and different effects between individual components have been observed: synergism (positive effect), additivism (summary effect) and antagonism (negative effect). Higher oxidative stability of the lipid substrate was obtained in the presence of the new antioxidant compositions of the studied compounds with dl-α-tocopherol and l-ascorbic acid. The role of each component in the antioxidant compositions of ternary mixtures has been identified by using new equations composed by the authors., Conclusion: All ternary mixtures demonstrate synergism as a result of continuous regeneration of dl-α-tocopherol from the studied antioxidants and l-ascorbic acid. Theoretical calculations have been probed as indicators of the expected effects between the individual components in a binary mixture. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C 2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K i , 1.93 ± 0.29 µM for Plm II; K i , 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K i , 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC 50 , 2.27 ± 0.95 µM for 10f; IC 50 , 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC 50 value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules., (Copyright © 2018. Published by Elsevier Ltd.)

We have previously demonstrated that human heat shock protein 90 (HSP90), an intracellular self protein, is the target of cellular and humoral autoimmune responses in patients with carotid atherosclerosis. In this study, we evaluated in vitro whether oxidative stress, a feature of atherosclerotic plaque, alters HSP90 expression in endothelial cells, thus inducing surface localization of this molecule and whether the antioxidant compound 7,8-dihydroxy-4-methylcoumarin (7,8-DHMC) is able to prevent oxidative stress-induced alterations of HSP90 localization. By the use of flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, and semiquantitative reverse-transcription polymerase chain reaction, we demonstrated that exposure of human umbilical vein endothelial cells (HUVEC) to the prooxidant compound H 2 O 2 upregulated HSP90 surface expression and reduced its secretion without altering HSP90 gene expression and intracytoplasmic protein levels. Pretreatment of HUVEC with 7,8-DHMC prevented H 2 O 2 -induced alterations of HSP90 cellular distribution and secretion. Our results suggest that the strong oxidative conditions of atherosclerotic plaques promote the upregulation of HSP90 surface expression on endothelial cells, thus rendering the protein a possible target of autoimmune reactions. The antioxidant 7,8-DHMC, by preventing oxidative-stress-triggered HSP90 surface upregulation, may be useful to counteract possible autoreactive reactions to HSP90.

Background: There are growing demands for predicting the prospects of achieving the global elimination of neglected tropical diseases as a result of the institution of large-scale nation-wide intervention programs by the WHO-set target year of 2020. Such predictions will be uncertain due to the impacts that spatial heterogeneity and scaling effects will have on parasite transmission processes, which will introduce significant aggregation errors into any attempt aiming to predict the outcomes of interventions at the broader spatial levels relevant to policy making. We describe a modeling platform that addresses this problem of upscaling from local settings to facilitate predictions at regional levels by the discovery and use of locality-specific transmission models, and we illustrate the utility of using this approach to evaluate the prospects for eliminating the vector-borne disease, lymphatic filariasis (LF), in sub-Saharan Africa by the WHO target year of 2020 using currently applied or newly proposed intervention strategies. METHODS AND RESULTS: We show how a computational platform that couples site-specific data discovery with model fitting and calibration can allow both learning of local LF transmission models and simulations of the impact of interventions that take a fuller account of the fine-scale heterogeneous transmission of this parasitic disease within endemic countries. We highlight how such a spatially hierarchical modeling tool that incorporates actual data regarding the roll-out of national drug treatment programs and spatial variability in infection patterns into the modeling process can produce more realistic predictions of timelines to LF elimination at coarse spatial scales, ranging from district to country to continental levels. Our results show that when locally applicable extinction thresholds are used, only three countries are likely to meet the goal of LF elimination by 2020 using currently applied mass drug treatments, and that switching to more intensive drug regimens, increasing the frequency of treatments, or switching to new triple drug regimens will be required if LF elimination is to be accelerated in Africa. The proportion of countries that would meet the goal of eliminating LF by 2020 may, however, reach up to 24/36 if the WHO 1% microfilaremia prevalence threshold is used and sequential mass drug deliveries are applied in countries., Conclusions: We have developed and applied a data-driven spatially hierarchical computational platform that uses the discovery of locally applicable transmission models in order to predict the prospects for eliminating the macroparasitic disease, LF, at the coarser country level in sub-Saharan Africa. We show that fine-scale spatial heterogeneity in local parasite transmission and extinction dynamics, as well as the exact nature of intervention roll-outs in countries, will impact the timelines to achieving national LF elimination on this continent.

The aim of this study is to determine, and to compare the protective effects of eight 4-methylcoumarins and four related compounds as radical scavengers and chain-breaking antioxidants. The main kinetic parameters of their radical scavenging activity (as % RSA, stoichiometry, n, and rate constants of reaction with DPPH radical, k RSA ) and of chain breaking antioxidant activity (as antioxidant efficiency, PF and reactivity, ID), have been determined and discussed. The RSA study has been conducted at physiological temperature (37 °С) towards DPPH radical and the tested compounds are separated into three main groups: with strong activity (% RSA > 40%); with moderate activity (20% < % RSA > 40%) and with weak activity (% RSA < 20%). Chain-breaking antioxidant activities of the studied compounds have been evaluated during bulk phase lipid (triacylglycerols of sunflower oil, TGSO) autoxidation at 80 °C. All results obtained are compared with those for standard and known inhibitors of oxidation processes, e.g. caffeic and p-coumaric acids, α-tocopherol and butylated hydroxytoluene (BHT). On the basis of a comparative analysis with standard antioxidants, the differences in the radical scavenging and antioxidant abilities of the studied compounds have been discussed and reaction mechanisms proposed. All structures are optimized at UB3LYP/6-31 + G(d,p) level in gas phase and in acetone solution to study the solvation effects., (Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Concern is growing regarding the prospects of achieving the global elimination of lymphatic filariasis (LF) by 2020. Apart from operational difficulties, evidence is emerging which points to unique challenges that could confound achieving LF elimination as extinction targets draw near. Diethylcarbamazine (DEC)-medicated salt may overcome these complex challenges posed by the endgame phase of parasite elimination. We calibrated LF transmission models using Bayesian data-model assimilation techniques to baseline and follow-up infection data from 11 communities that underwent DEC salt medication. The fitted models were used to assess the utility of DEC salt treatment for achieving LF elimination, in comparison with other current and proposed drug regimens, during the endgame phase. DEC-medicated salt consistently reduced microfilaria (mf) prevalence from 1% mf to site-specific elimination thresholds more quickly than the other investigated treatments. The application of DEC salt generally required less than one year to achieve site-specific LF elimination, while annual and biannual MDA options required significantly longer durations to achieve the same task. The use of DEC-medicated salt also lowered between-site variance in extinction timelines, especially when combined with vector control. These results indicate that the implementation of DEC-medicated salt, where feasible, can overcome endgame challenges facing LF elimination programs.

A series of phthalimide analogues, novelized with high-valued bioactive scaffolds was synthesized by means of click-chemistry under non-conventional microwave heating and evaluated as noteworthy growth inhibitors of Plasmodium falciparum (3D7 and W2) in culture. Analogues 6a, 6h and 6 u showed highest activity to inhibit the growth of the parasite with IC 50 values in submicromolar range. Structure-activity correlation indicated the necessity of unsubstituted triazoles and leucine linker to obtain maximal growth inhibition of the parasite. Notably, phthalimide 6a and 6u selectively inhibited the ring-stage growth and parasite maturation. On other hand, phthalimide 6h displayed selective schizonticidal activity. Besides, they displayed synergistic interactions with chloroquine and dihydroartemisinin against parasite. Additional in vivo experiments using P. berghei infected mice showed that administration of 6h and 6u alone, as well as in combination with dihydroartemisinin, substantially reduced the parasite load. The high antimalarial activity of 6h and 6u, coupled with low toxicity advocate their potential role as novel antimalarial agents, either as standalone or combination therapies.

Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we now report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogues. Anti- Aspergillus activity was observed for an optically enriched derivative, (-)- S -2-(2',4'-difluorophenyl)-1-hexyl-amino-3-(1‴,2‴,4‴)triazol-1‴-yl-propan-2-ol, which exhibits MIC values of 15.6 μg/ml and 7.8 μg/disc in broth microdilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1,000 μg/ml. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analogue exhibited improved antifungal activity against Aspergillus fumigatus (MIC, 1.63 μg/ml). These results not only demonstrate the ability of biocatalytic approaches to yield novel, optically enriched fluconazole derivatives but also suggest that enantiomerically pure fluconazole derivatives, and their nanotized counterparts, exhibiting anti- Aspergillus activity may have reduced toxicity., (Copyright © 2017 American Society for Microbiology.)

Background: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings., Methods: We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens., Findings: In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low., Interpretation: Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme., Funding: Bill & Melinda Gates Foundation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Mathematical models of parasite transmission provide powerful tools for assessing the impacts of interventions. Owing to complexity and uncertainty, no single model may capture all features of transmission and elimination dynamics. Multi-model ensemble modelling offers a framework to help overcome biases of single models. We report on the development of a first multi-model ensemble of three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and evaluate its predictive performance in comparison with that of the constituents using calibration and validation data from three case study sites, one each from the three major LF endemic regions: Africa, Southeast Asia and Papua New Guinea (PNG). We assessed the performance of the respective models for predicting the outcomes of annual MDA strategies for various baseline scenarios thought to exemplify the current endemic conditions in the three regions. The results show that the constructed multi-model ensemble outperformed the single models when evaluated across all sites. Single models that best fitted calibration data tended to do less well in simulating the out-of-sample, or validation, intervention data. Scenario modelling results demonstrate that the multi-model ensemble is able to compensate for variance between single models in order to produce more plausible predictions of intervention impacts. Our results highlight the value of an ensemble approach to modelling parasite control dynamics. However, its optimal use will require further methodological improvements as well as consideration of the organizational mechanisms required to ensure that modelling results and data are shared effectively between all stakeholders., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Despite the substantial progress over the time, malaria remains a major public health concern and causing hundreds of thousands of deaths. Resistance to the available antimalarial therapy increases threat to the global public health., Objective: Overview of currently available antimalarials., Method: Literary survey., Results: The summarized data about different types of antimalarial therapies and their efficiency and modes of action., Conclusion: Despite the seemingly large number of the drugs currently available for malaria treatment, this arsenal is limited due to the narrow variation of their mechanism of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Enzymes, being remarkable catalysts, are capable of accepting a wide range of complex molecules as substrates and catalyze a variety of reactions with a high degree of chemo-, stereo- and regioselectivity in most of the reactions. Biocatalysis can be used in both simple and complex chemical transformations without the need for tedious protection and deprotection chemistry that is very common in traditional organic synthesis. This current review highlights the applicability of one class of biocatalysts viz."lipases" in synthetic transformations, the resolution of pharmaceutically important small molecules including polyphenols, amides, nucleosides and their precursors, the development of macromolecular systems (and their applications as drug/gene carriers), flame retardants, polymeric antioxidants and nanocrystalline solar cells, etc.

New isatin-triazole based hybrids have been synthesized and evaluated for their inhibitory activity of TNF-α induced expression of Intercellular Adhesion Molecule-1 (ICAM-1) on the surface of human endothelial cells. Structure-activity relationship (SAR) studies revealed that the presence of the electron-attracting bromo substituent at position-5 of the isatin moiety played an important role in enhancing the anti-inflammatory potential of the synthesized compounds. Z-1-[3-(1H-1,2,4-Triazol-1-yl)propyl]-5-bromo-3-[2-(4-methoxyphenyl)hydrazono]indolin-2-one (19) with an IC50 = 20 μM and 89% ICAM-1 inhibition with MTD at 200 μM was found to be the most potent of all the synthesized derivatives. Introduction of 1,2,4-triazole ring and electron-donating methoxy group on the phenylhydrazone moiety resulted in four-fold increase of the anti-inflammatory activity.

Highly regioselective acylation has been observed in 7,8-dihydroxy-4-methylcoumarin (DHMC) by the lipase from Rhizopus oryzae suspended in tetrahydrofuran (THF) at 45 °C using six different acid anhydrides as acylating agents. The acylation occurred regioselectively at one of the two hydroxy groups of the coumarin moiety resulting in the formation of 8-acyloxy-7-hydroxy-4-methylcoumarins, which are important bioactive molecules for studying biotansformations in animals, and are otherwise very difficult to obtain by only chemical steps. Six monoacylated, monohydroxy 4-methylcoumarins have been biocatalytically synthesised and identified on the basis of their spectral data and X-ray crystal analysis.

We study changes in the bifurcations of seasonally driven compartmental epidemic models, where the transmission rate is modulated temporally. In the presence of periodic modulation of the transmission rate, the dynamics varies from periodic to chaotic. The route to chaos is typically through period doubling bifurcation. There are coexisting attractors for some sets of parameters. However in the presence of quasiperiodic modulation, tori are created in place of periodic orbits and chaos appears via finite torus doublings. Strange nonchaotic attractors (SNAs) are created at the boundary of chaotic and torus dynamics. Multistability is found to be reduced as a function of quasiperiodic modulation strength. It is argued that occurrence of SNAs gives an opportunity of asymptotic predictability of epidemic growth even when the underlying dynamics is strange.

We have demonstrated Ru(4+) induced colossal magnetoimpedance (MI) at room temperature in a ∼1 Tesla magnetic field with a pulsed laser deposited La0.7Ca0.3Mn0.7Ru0.3O3 thin film. This composition showed a large negative ∼12% MI in the low frequency range (<5 MHz), a colossal positive MI > 120% in the intermediate frequency range (5 MHz to ∼13 MHz) and a negative MI in the high frequency range (∼13 MHz to 40 MHz) at room temperature. XAS data confirmed the predominant Ru valence state was 4+ in La0.7Ca0.3Mn0.7Ru0.3O3. Ru(4+) induced (i) charge carrier localization and (ii) reduced hole carrier density enhances the MI in this composition, which otherwise was not significant in mixed valences Mn(3+)/Mn(4+) containing La0.7Ca0.3MnO3 and Ru(4+)/Ru(5+) and Mn(3+)/Mn(4+) mixed valences containing Ru = 0.1 and Ru = 0.2 compositions in La0.7Ca0.3Mn1-xRuxO3 (0 ≤x≤ 0.3) thin films.

The epidemiology of dengue fever is characterized by highly seasonal, multi-annual fluctuations, and the irregular circulation of its four serotypes. It is believed that this behaviour arises from the interplay between environmental drivers and serotype interactions. The exact mechanism, however, is uncertain. Constraining mathematical models to patterns characteristic to dengue epidemiology offers a means for detecting such mechanisms. Here, we used a pattern-oriented modelling (POM) strategy to fit and assess a range of dengue models, driven by combinations of temporary cross protective-immunity, cross-enhancement, and seasonal forcing, on their ability to capture the main characteristics of dengue dynamics. We show that all proposed models reproduce the observed dengue patterns across some part of the parameter space. Which model best supports the dengue dynamics is determined by the level of seasonal forcing. Further, when tertiary and quaternary infections are allowed, the inclusion of temporary cross-immunity alone is strongly supported, but the addition of cross-enhancement markedly reduces the parameter range at which dengue dynamics are produced, irrespective of the strength of seasonal forcing. The implication of these structural uncertainties on predicted vulnerability to control is also discussed. With ever expanding spread of dengue, greater understanding of dengue dynamics and control efforts (e.g. a near-future vaccine introduction) has become critically important. This study highlights the capacity of multi-level pattern-matching modelling approaches to offer an analytic tool for deeper insights into dengue epidemiology and control.

Background: The current WHO-led initiative to eradicate the macroparasitic disease, lymphatic filariasis (LF), based on single-dose annual mass drug administration (MDA) represents one of the largest health programs devised to reduce the burden of tropical diseases. However, despite the advances made in instituting large-scale MDA programs in affected countries, a challenge to meeting the goal of global eradication is the heterogeneous transmission of LF across endemic regions, and the impact that such complexity may have on the effort required to interrupt transmission in all socioecological settings., Methods: Here, we apply a Bayesian computer simulation procedure to fit transmission models of LF to field data assembled from 18 sites across the major LF endemic regions of Africa, Asia and Papua New Guinea, reflecting different ecological and vector characteristics, to investigate the impacts and implications of transmission heterogeneity and complexity on filarial infection dynamics, system robustness and control., Results: We find firstly that LF elimination thresholds varied significantly between the 18 study communities owing to site variations in transmission and initial ecological parameters. We highlight how this variation in thresholds lead to the need for applying variable durations of interventions across endemic communities for achieving LF elimination; however, a major new result is the finding that filarial population responses to interventions ultimately reflect outcomes of interplays between dynamics and the biological architectures and processes that generate robustness/fragility trade-offs in parasite transmission. Intervention simulations carried out in this study further show how understanding these factors is also key to the design of options that would effectively eliminate LF from all settings. In this regard, we find how including vector control into MDA programs may not only offer a countermeasure that will reliably increase system fragility globally across all settings and hence provide a control option robust to differential locality-specific transmission dynamics, but by simultaneously reducing transmission regime variability also permit more reliable macroscopic predictions of intervention effects., Conclusions: Our results imply that a new approach, combining adaptive modelling of parasite transmission with the use of biological robustness as a design principle, is required if we are to both enhance understanding of complex parasitic infections and delineate options to facilitate their elimination effectively.

A microwave-assisted highly efficient intermolecular domino carbopalladation/C-H functionalization sequence has been developed to access bis-heteroaryl frameworks in a single operation. The reaction involves carbopalladation of the halogenated acrylamides or phenylpropiolamides by the Pd(0) catalysis, followed by the direct (hetero)arylation to give products with good to excellent yields. The synthetic utility of this method was also extended towards the application of the Ugi-adduct as the starting material., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination 'as a public health problem' when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models' predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020.