Non-Markovian polymer reaction kinetics

Describing the kinetics of polymer reactions, such as the formation of loops and hairpins in nucleic acids or polypeptides, is complicated by the structural dynamics of their chains. Although both intramolecular reactions, such as cyclization, and intermolecular reactions have been studied extensively, both experimentally and theoretically, there is to date no exact explicit analytical treatment of transport-limited polymer reaction kinetics, even in the case of the simplest (Rouse) model of monomers connected by linear springs. We introduce a new analytical approach to calculate the mean reaction time of polymer reactions that encompasses the non-Markovian dynamics of monomer motion. This requires that the conformational statistics of the polymer at the very instant of reaction be determined, which provides, as a by-product, new information on the reaction path. We show that the typical reactive conformation of the polymer is more extended than the equilibrium conformation, which leads to reaction times significantly shorter than predicted by the existing classical Markovian theory.Comment: Main text (7 pages, 5 figures) + Supplemantary Information (13 pages, 2 figures

"Practical Knowledge" and Perceptions of Antibiotics and Antibiotic Resistance Among Drugsellers in Tanzanian Private Drugstores.

Studies indicate that antibiotics are sold against regulation and without prescription in private drugstores in rural Tanzania. The objective of the study was to explore and describe antibiotics sale and dispensing practices and link it to drugseller knowledge and perceptions of antibiotics and antibiotic resistance. Exit customers of private drugstores in eight districts were interviewed about the drugstore encounter and drugs bought. Drugsellers filled in a questionnaire with closed- and open-ended questions about antibiotics and resistance. Data were analyzed using mixed quantitative and qualitative methods. Of 350 interviewed exit customers, 24% had bought antibiotics. Thirty percent had seen a health worker before coming and almost all of these had a prescription. Antibiotics were dispensed mainly for cough, stomachache, genital complaints and diarrhea but not for malaria or headache. Dispensed drugs were assessed as relevant for the symptoms or disease presented in 83% of all cases and 51% for antibiotics specifically. Non-prescribed drugs were assessed as more relevant than the prescribed. The knowledge level of the drugseller was ranked as high or very high by 75% of the respondents. Seventy-five drugsellers from three districts participated. Seventy-nine percent stated that diseases caused by bacteria can be treated with antibiotics but 24% of these also said that antibiotics can be used for treating viral disease. Most (85%) said that STI can be treated with antibiotics while 1% said the same about headache, 4% general weakness and 3% 'all diseases'. Seventy-two percent had heard of antibiotic resistance. When describing what an antibiotic is, the respondents used six different kinds of keywords. Descriptions of what antibiotic resistance is and how it occurs were quite rational from a biomedical point of view with some exceptions. They gave rise to five categories and one theme: Perceiving antibiotic resistance based on practical experience. The drugsellers have considerable "practical knowledge" of antibiotics and a perception of antibiotic resistance based on practical experience. In the process of upgrading private drugstores and formalizing the sale of antibiotics from these outlets in resource-constrained settings, their "practical knowledge" as well as their perceptions must be taken into account in order to attain rational dispensing practices

Hypothalamic control of food intake in cats and monkeys

The role of the central nervous system in regulating food intake was probably suggested first by the discovery that either obesity or emaciation may occur in patients with nervous diseases. For a while these observations were not properly evaluated, because emphasis was laid upon the obesity as such, or the leanness, rather than upon the changed eating habits responsible for the clinical picture. Interest was focused on the hypothalamic region by the experimental studies of many workers (Hetherington, 1941; Hetherington & Ranson, 1940, 1942 a, b; Brobeck, Tepperman & Long, 1943; Kennedy, 1950; Ranson, Fisher & Ingram, 1938) who showed that bilateral lesions in the medial hypothalamus, especially lesions in or ventro-lateral to the ventromedial nucleus, resulted in obesity. The confusion introduced by the notion that pituitary disturbances caused obesity was also clarified by Hetherington (1943), who showed that the hypophysis is in no way directly concerned with the pathogenesis of obesity following injury to the base of brain. Brobeck et al. (1943) demonstrated that this hypothalamic obesity was due to increased food intake (hypothalamic hyperphagia) rather than to disturbances in the fat, carbohydrate or intermediary metabolism. From the time of its discovery this hyperphagia was assumed to be a release phenomenon brought about through the destruction of an inhibitory mechanism.The existence of another mechanism in the lateral hypothalamus of the rat, which controls the 'instinct' or the 'urge' to eat, was demonstrated by Anand & Brobeck (1951 a, b). They showed that bilateral destruction of a well localized area in the lateral hypothalamus, at the same rostro-caudal level as the ventro-medial nucleus, produces complete aphagia and death due to starvation, in spite of the availability of food. It was also observed that of the two mechanisms the lateral one exerts the more basic type of control over food intake and the medial one (inhibitory) produces its effects only when the lateral is intact. The lateral mechanism is designated a 'feeding centre', or even an 'appetite centre', while the medial one is called a 'satiety centre'. Joliffe named the two, together, the 'appestat'. The present study was undertaken to determine, whether similar mechanisms exist in the hypothalamic regions of higher mammals, cats and monkeys, and also whether they are modified by the more highly evolved higher nervous centres

Prolapse or incontinence: what affects sexual function the most?

Introduction and hypothesis Pelvic organ prolapse (POP) and stress urinary incontinence (SUI) adversely affect sexual function in women. Comparative studies of the two subgroups are few and results are conflicting. The aim of this study was to compare the effect of POP and SUI on the sexual function of women undergoing surgery for these conditions. Methods The study population comprised women with POP or SUI in a tertiary referral hospital in the UK. Women who underwent SUI surgery had no symptoms of POP and had urodynamically proven stress incontinence. Patients with POP had ≥ stage 2 prolapse, without bothersome urinary symptoms. Pre-operative data on sexual function were collected and compared using an electronic pelvic floor assessment questionnaire (ePAQ). The incidence of sexual dysfunction and comparison of symptoms in both groups were calculated using the Mann–Whitney U test. Results Three hundred and forty-three women undergoing surgery for either SUI or POP were included. Patients were age-matched, with 184 undergoing SUI surgery (age range 33–77 years) and 159 POP surgery (age range 27–78 years; p = 0.869). The overall impact of POP and SUI was not significantly different in the two subgroups (p = 0.703). However, both patients (73 % vs 36 %; p = 0.00) and partners (50 % vs 24 %; p = 0.00) avoid intercourse significantly more frequently in cases with POP compared with SUI. This did not have a significant impact on quality of life. Conclusions The impact of bothersome SUI or POP on sexual function was found to be similar, but patient and partner avoidance in women with POP was greater than those with SUI

Optimised laser microdissection of the human ocular surface epithelial regions for microarray studies

Background The most important challenge of performing insitu transcriptional profiling of the human ocular surface epithelial regions is obtaining samples in sufficient amounts, without contamination from adjacent tissue, as the region of interest is microscopic and closely apposed to other tissues regions. We have effectively collected ocular surface (OS) epithelial tissue samples from the Limbal Epithelial Crypt (LEC), limbus, cornea and conjunctiva of post-mortem cadaver eyes with laser microdissection (LMD) technique for gene expression studies with spotted oligonucleotide microarrays and Gene 1.0 ST arrays. Methods Human donor eyes (4 pairs for spotted oligonucleotide microarrays, 3 pairs for Gene 1.0 ST arrays) consented for research were included in this study with due ethical approval of the Nottingham Research Ethics Committee. Eye retrieval was performed within 36 hours of post-mortem period. The dissected corneoscleral buttons were immersed in OCT media and frozen in liquid nitrogen and stored at −80°C till further use. Microscopic tissue sections of interest were taken on PALM slides and stained with Toluidine Blue for laser microdissection with PALM microbeam systems. Optimisation of the laser microdissection technique was crucial for efficient and cost effective sample collection. Results The starting concentration of RNA as stipulated by the protocol of microarray platforms was taken as the cut-off concentration of RNA samples in our studies. The area of LMD tissue processed for spotted oligonucleotide microarray study ranged from 86,253 μm2 in LEC to 392,887 μm2 in LEC stroma. The RNA concentration of the LMD samples ranged from 22 to 92 pg/μl. The recommended starting concentration of the RNA samples used for Gene 1.0 ST arrays was 6 ng/5 μl. To achieve the desired RNA concentration the area of ocular surface epithelial tissue sample processed for the Gene 1.0 ST array experiments was approximately 100,0000 μm2 to 130,0000 μm2. RNA concentration of these samples ranged from 10.88 ng/12 μl to 25.8 ng/12 μl, with the RNA integrity numbers (RIN) for these samples from 3.3 to 7.9. RNA samples with RIN values below 2, that had failed to amplify satisfactorily were discarded. Conclusions The optimised protocol for sample collection and laser microdissection improved the RNA yield of the insitu ocular surface epithelial regions for effective microarray studies on spotted oligonucleotide and affymetrix platforms

Editorial: Beyond borders: exploring diverse roles of heterocyclic compounds in combatting infections and cancer

This Research Topic aimed to explore the advancements and applications of heterocyclic compounds, highlighting their importance in contemporary medicinal chemistry. The objective was to examine their diverse roles in tackling two major health concerns: infectious diseases and cancer. Currently, cancer and infectious diseases are among the most prevalent and challenging health conditions, significantly affecting the overall wellbeing of the population. According to the World Health Organization (WHO), approximately 20 million new cancer cases were diagnosed globally in 2022, with 9.7 million deaths attributed to the disease. Projections suggest that by 2050, the number of cancer cases could rise to 35 million (Seigel et al., 2023). Antimicrobial resistance (AMR) is recognized as one of the top ten global health threats, posing significant risks not only to human health but also to environmental wellbeing. It is classified as a quintessential One Health challenge. The most concerning pathogens, characterized by multidrug resistance (MDR), extended-drug resistance, and even pan-drug resistance phenotypes, are collectively referred to by the acronym ESCAPE, encompassing Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae (De Oliveira et al., 2020). Recent developments in this area have shown the potential of heterocyclic compounds to offer more targeted and effective treatments with fewer side effects. Therefore, this Research Topic invited papers that showcased recent progress in medicinal and natural product chemistry, including the isolation and characterization, design, synthesis, and application of heterocyclic compounds as promising anti-infective and anticancer agents

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

Synthesis of Nitrogenated Heterocycles by Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)haloimines

Highly optically enriched, protected, nitrogenated heterocycles with different ring sizes have been synthesized by a very efficient methodology consisting of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. N-Protected aziridines, pyrrolidines, piperidines, and azepanes bearing aromatic, heteroaromatic, and aliphatic substituents have been obtained in very high yields and diastereomeric ratios up to >99:1. The free heterocycles can be easily obtained by a simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results by changing the absolute configuration of the sulfur atom of the sulfinyl group.This work was generously supported by the Spanish Ministerio de Ciencia e Innovación (MICINN; grant no. CONSOLIDER INGENIO 2010, CSD2007-00006, CTQ2007-65218 and CTQ2011-24151) and the Generalitat Valenciana (PROMETEO/2009/039 and FEDER). O.P. thanks the Spanish Ministerio de Educación for a predoctoral fellowship (grant no. AP-2008-00989)

Essential mineral and haemato-biochemical status of ill-Thrift buffalo calves in the fluoride endemic south-west Punjab, India

The present study aimed to evaluate essential mineral and haemato-biochemical status of the ill-thrift buffalo calves (n=21) in comparison to the healthy control (n=63) in the fluoride endemic south-west Punjab, India. Blood samples of the calves were analysed for plasma fluoride, calcium, phosphorus, magnesium, copper, molybdenum, zinc, iron, manganese, arsenic, ceruloplasmin and alkaline phosphatase activity, urea nitrogen, creatinine, glucose, cholesterol, triglycerides, serum total proteins and albumin, and Hb, PCV, TEC. Mean fluoride concentration in the ill-thrift calves (0.20±0.07 μgml-1) was higher than the physiological limit of 0.10 μgml-1 and also was significantly (P<0.05) higher than that in the healthy control (0.07±0.01 μgml-1). There was significant reduction (P<0.05) in plasma Pi, Zn, ceruloplasmin activity, Hb and TEC concentrations in the ill-thrift calves in comparison to the healthy control. The alkaline phosphatase activity was significantly (P<0.05) higher in the ill-thrift calves. It is concluded that higher plasma fluoride concentrations reflected moderately high fluoride intake which resulted in impaired metabolism of essential minerals Cu, Zn and P, and depressed haematopoitic activity that might caused ill-thrift in the buffalo calves from the fluoride endemic region of south-west Punjab in India

The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Replication fork stalling and accumulation of single-stranded DNA trigger the S phase checkpoint, a signalling cascade that, in budding yeast, leads to the activation of the Rad53 kinase. Rad53 is essential in maintaining cell viability, but its targets of regulation are still partially unknown. Here we show that Rad53 drives the hyper-SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε, principally following replication forks stalling induced by nucleotide depletion. Pol2 is the main target of SUMOylation within the replisome and its modification requires the SUMO-ligase Mms21, a subunit of the Smc5/6 complex. Moreover, the Smc5/6 complex co-purifies with Pol ε, independently of other replisome components. Finally, we map Pol2 SUMOylation to a single site within the N-terminal catalytic domain and identify a SUMO-interacting motif at the C-terminus of Pol2. These data suggest that the S phase checkpoint regulate Pol ε during replication stress through Pol2 SUMOylation and SUMO-binding abilit