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Abstract Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M1 receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish (Danio rerio) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a, c, reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.

Background: Zebrafish have become a key model organism in neuroscience research because of their unique advantages. Their genetic, anatomical, and physiological similarities to humans, coupled with their rapid development and transparent embryos, make them an excellent tool for investigating various aspects of neurobiology. They have specifically emerged as a valuable and versatile model organism in biomedical research, including the study of neurological disorders such as multiple sclerosis. Multiple sclerosis is a chronic autoimmune disease known to cause damage to the myelin sheath that protects the nerves in the brain and spinal cord. Objective: This review emphasizes the importance of continued research in both in vitro and in vivo models to advance our understanding of MS and develop effective treatments, ultimately improving the quality of life for those affected by this debilitating disease. Conclusions: Recent studies show the significance of zebrafish as a model organism for investigating demyelination and remyelination processes, providing new insights into MS pathology and potential therapies.

Raccoons are host to diverse gastrointestinal parasites, but little is known about the ecology of these parasites in terms of their interactions with each other during coinfections, their interactions with host physiology and environmental factors, and their impact on raccoon health and survival. As a first step, we investigated the patterns of parasite infection and their demographic distribution in an urban-suburban population of raccoons trapped in the summers and autumns of 2018 and 2019. We collected faecal samples, demographic data, morphometric measurements, and blood smears, and used GPS data to classify trapping location by land cover type. Faecal floats were performed to detect and quantify gastrointestinal nematode eggs and coccidia oocysts, and white blood cell differentials were performed on blood smears to characterise white blood cell distributions. Data were analysed cross-sectionally and, where possible, longitudinally, using generalised linear models. Overall, 62.6% of sampled raccoons were infected with gastrointestinal nematodes, and 82.2% were infected with gastrointestinal coccidia. We analysed predictors of infection status and faecal egg count for three different morphotypes of nematode—Baylisascaris, strongyle, and capillariid nematodes—and found that infection status and egg count varied with Year, Month, Age class, Land cover, and coinfection status, though the significance of these predictors varied between nematode types. Gastrointestinal coccidia prevalence varied with Year, Month, Age class, strongyle infection status, and capillariid infection status. Coccidia oocyst counts were lower in adults and in October, but higher in females and in raccoons trapped in areas with natural land cover; furthermore, coccidia oocysts were positively associated with capillariid faecal egg counts. We found no evidence that gastrointestinal parasites influenced raccoon body condition or overwinter mortality, and so conclude that raccoons, though harbouring diverse and abundant gastrointestinal parasites, may be relatively tolerant of these parasites.

Abstract Background Uganda has registered an increased investment in family planning (FP) programs, which has contributed to improvement in knowledge of modern contraceptive methods being nearly universal. However, this has not matched the uptake of modern methods or the reduction in the unmet need for FP. This may be explained by the different influences which include health workers, family, and friends. Due to the limited uptake of contraceptive methods, a program on improving awareness, access to, and uptake of modern contraceptives is being implemented in selected regions in Uganda. We, therefore, conducted a formative study to determine the influences on contraceptive uptake at the onset of this program. Methods Using a qualitative study design, we conducted thirty-two focus group discussions and twenty-one in-depth interviews involving men and women of reproductive age. We also carried out twenty-one key informant interviews with people involved in FP service delivery. Data was collected in four districts where implementation of the program was to take place. Audio recorders were used to collect data and tools were translated into local languages. A codebook was developed, and transcripts were coded in vivo using the computer software Atlas-ti version 7 before analysis. Ethical clearance was obtained from institutional review boards and informed consent was sought from all participants. Results From the study, most married people mentioned health workers as their main influence while adolescents reported their peers and friends. Religious leaders and mothers-in-law were reported to mainly discourage people from taking up modern contraceptive methods. The cultural value attached to having many children influenced the contraceptive use decision among people in rural settings. Other influences included a person’s experience and housing. Conclusions Health workers, religious leaders, and mothers determine the uptake of contraceptive services. The study recommends the consideration of the role of these influences in the design of FP program interventions as well as more involvement of health workers in sensitization of communities about contraceptive methods.

Introduction A negative correlation exists between functional outcomes and leg length discrepancy (LLD) following hip fracture repair. We have assessed the effects of LLD following hip fracture repair in elderly patients on 3-meter walking time, standing time, activities of daily living (ADL), and instrumental activities of daily living (IADL). Methods One hundred sixty-nine patients enrolled in the STRIDE trial were identified with femoral neck, intertrochanteric, and subtrochanteric fractures that were treated with partial hip replacement, total hip replacement, cannulated screws, or intramedullary nail. Baseline patient characteristics recorded included age, sex, body mass index Charlson comorbidity index (CCI) score. ADL, IADL, grip strength, sit-to-stand time, 3-meter walking time and return to ambulation status were measured at 1 year after surgery. LLD was measured on final follow-up radiographs by either the sliding screw telescoping distance or the difference from a trans-ischial line to the lesser trochanters, and was analyzed as a continuous variable using regression analysis. Results Eighty eight patients (52%) had LLD 10 mm. Age, sex, BMI, Charlson score, and ambulation status had no significant impact on LLD occurrence. Type of procedure and fracture type did not correlate with severity of LLD. Having a larger LLD was not found to have a significant impact on post-operative ADL ( P = .60), IADL ( P = .08), sit-to-stand time ( P = .90), grip strength ( P = .14) and return to former ambulation status ( P = .60), but did have a statistically significant impact on 3-meter walking time ( P = .006). Discussion LLD after hip fracture was associated with reduced gait speed but did not affect many parameters associated with recovery. Continued efforts to restore leg length after hip fracture repair are likely to be beneficial.

BackgroundExtended-spectrum beta-lactamase-producing Escherichia coli (ESBL-Ec) represents a significant global public health concern. The epidemiology of ESBL-Ec in Uganda is not well understood although it is harbored by humans, animals, and the environment. This study explains the epidemiology of ESBL-Ec using a one health approach in selected farming households in Wakiso district, Uganda.MethodologyEnvironmental, human, and animal samples were collected from 104 households. Additional data were obtained using observation checklists and through interviews with household members using a semi-structured questionnaire. Surface swabs, soil, water, human and animal fecal samples were introduced onto ESBL chromogenic agar. The isolates were identified using biochemical tests and double-disk synergy tests. To assess associations, prevalence ratios (PRs) were computed using a generalized linear model (GLM) analysis with modified Poisson and a log link with robust standard errors in R software.ResultsApproximately 83% (86/104) households had at least one positive ESBL-Ec isolate. The overall prevalence of ESBL-Ec at the human-animal-environment interface was approximately 25.0% (95% CI: 22.7-28.3). Specifically, humans, animals and the environment had an ESBL-Ec prevalence of 35.4%, 55.4%, and 9.2% respectively. Having visitors (adj PR = 1.19, 95% CI: 1.04-1.36), utilizing veterinary services (adj PR = 1.39, 95% CI: 1.20-1.61) and using animal waste for gardening (adj PR = 1.29, 95% CI: 1.05-1.60) were positively associated with household ESBL-Ec contamination. Covering the drinking water container with a lid (adj PR = 0.84 95% CI: 0.73-0.96) was associated with absence of ESBL-Ec in a household.ConclusionThere is wider dissemination of ESBL-Ec in the environment, humans, and animals, indicating poor infection prevention and control (IPC) measures in the area. Improved collaborative one health mitigation strategies such as safe water chain, farm biosecurity, household and facility-based IPC measures are recommended to reduce the burden of antimicrobial resistance at community level.

Recent studies have demonstrated an important role for vitamin C in the epigenetic regulation of cancer-related genes via DNA demethylation by the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes. DNA methyltransferase (DNMT) reverses this, increasing DNA methylation and decreasing gene expression. Dual oxidase (DUOX) enzymes produce hydrogen peroxide (H2O2) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH−, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH− to further increase DUOX expression and cytotoxicity of PDAC. PDAC cells demonstrated dose-dependent increases in DUOX mRNA and protein expression when treated with DNMT inhibitors. PDAC cells treated with P-AscH− + DNMT inhibitors demonstrated increased DUOX expression, increased intracellular oxidation, and increased cytotoxicity in vitro and in vivo compared to either treatment alone. These findings suggest a potential therapeutic, epigenetic mechanism to treat PDAC.

Russian permafrost regions are unparalleled in extent, history of development, population presence, and the scale of economic activities. This special issue, «Permafrost Regions in Transition», provides a timely opportunity to (a) examine major issues associated with changing permafrost conditions in natural environments and areas of economic development; (b) present insights into new methods of permafrost investigations; and (c) describe new opportunities and risks threatening sustainable development of Arctic populations and industrial centers in Russia. The issue begins with papers focused on methods of permafrost research, followed by papers focused on examining changes in permafrost under natural conditions, and in Arctic settlements. The last two papers examine potential impacts of permafrost degradation on the Russian economy and potential health implications.

A catheter coating consisting of polydimethylsiloxane (PDMS) mixed with powdered metals silver and zinc has been investigated. The coating is easily applicable to existing silicone devices and effective in inhibiting the formation of biofilm. Following manufacturing of the coating, its surface materials characteristics were analyzed through scanning electron microscopy (SEM) and energy dispersive X-ray (EDX). The antibacterial properties of the coating were investigated by applying a thin film to the surface of a standard silicone catheter. A unique coating formulation of zinc and silver was found to inhibit biofilm and planktonic growth of E. coli over a six-day period, seemingly related to the release of heavy metal ions, generation of electric fields, hydrogen peroxide formation or combinations of these effects. Open-circuit cell potential for a zinc and silver foil was measured to be 1.2 V and 0.97 V within a deionized (DI) water and urine solution, respectively. Zone of inhibition experimental results suggest the possibility of silver ion diffusion when using mixed metals since bacteria formation is inhibited beyond the sample edge. Hydrogen peroxide measurements were taken over a period of 13 days for all samples. Samples containing zinc were found to produce hydrogen peroxide, a known antimicrobial agent. Wettability measurements of samples showed that the introduction of active materials lead to an increase of hydrophilicity, potentially affecting bacterial adhesion.

Background Previous studies of secular change in cranial size among black South Africans have produced conflicting results. Aim We re-examined cranial size change in this population during the 19th and 20th century by evaluating its relationship with individual year-of-birth, and the significance of trends among eight decennial cohorts. Subjects and methods This study is based on 102 male and 89 female adults born between 1865 and 1959. Linear regressions were employed to evaluate possible relationships between year-of-birth and cranial dimensions; ANOVAs were used to evaluate the significance of long-term trends among decennial cohorts. Results No analysis revealed a secular change in cranial length in either sex; however, the ANOVA for cranial length in the combined sex sample was significant. There is no secular trend in female cranial breadth, but males display a negative trend in this dimension. This results in a secular trend for increased male dolichocephaly. Conclusions The factors that underlie the negative secular trend in male cranial breadth and the absence of a secular trend in overall cranial size in this population are unclear. Nevertheless, these observations accord with findings related to stature and long bone strength in this population and are consistent with observations for other sub-Saharan African populations.

Background: Exercise-induced muscle damage (EIMD) commonly occurs following intense resistance exercise and is associated with decrements in exercise performance and delayed muscle recovery. Thus, practical methods to attenuate EIMD would prove useful to both training and athletic populations. Omega-3 (n-3) supplementation has been shown to mitigate EIMD with evidence of increasing efficacy at higher doses (up to 6 g/day). However, data of its efficacy in trained individuals is limited. Therefore, this study investigated the effects of 6 and 8 g of n-3 supplementation on markers of muscle damage and muscle recovery after eccentric resistance exercise in resistance-trained males. Methods: Using a double-blind, randomized, placebo-controlled design, 26 resistance trained males (23 ± 4 years; 173.6 ± 20.5 cm; 81.9 ± 9.7 kg; 14.2 ± 3.7% body fat) supplemented with 6 (n=10) or 8 g (n=7) of n-3 polyunsaturated fatty acids, or placebo (n=9) for 33 days. On day 30, participants performed a lower body muscle-damaging eccentric resistance exercise bout. Measures of muscle performance, soreness, and damage were taken pre-exercise on day 30 as well as on days 31–33, including vertical jump height (VJH), perceived muscle soreness (PMS), hip and knee range of motion (ROM), repetitions to fatigue (RTF) at 70% 1-RM, and serum creatine kinase (CK) while participants continued to supplement until day 33. Results: There were significant differences in VJH, PMS, and serum CK following the muscle-damaging exercise bout compared to pre-exercise (p0.05) differences between supplementation groups (6 g, 8 g, and placebo) at any time point post-exercise (day 31–33). There were no changes in hip and knee ROM or RTF at any time point or between groups. Vertical jump height and PMS returned to pre-exercise levels despite CK remaining elevated post-exercise. Conclusions: Thirty-three days of 6 and 8 g of n-3 supplementation did not attenuate EIMD or enhance muscle recovery following muscle-damaging eccentric resistance exercise in resistance-trained males. Further research using various n-3 supplementation durations, doses, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations may be needed to establish its efficacy in attenuating EIMD, which may vary between trained and untrained individuals. Furthermore, while circulating CK is commonly used to assess muscle damage, elevated CK levels may not reflect muscle recovery status following muscle-damaging exercise.

Continued yield increases of maize (Zea mays L.) will require higher planting populations, and enhancement of other agronomic inputs could alleviate density-induced stress. Row spacing, plant population, P-S-Zn fertility, K-B fertility, N fertility, and foliar protection were evaluated for their individual and cumulative impacts on the productivity of maize in a maize-soybean [Glycine max (L.) Merr.] rotation. An incomplete factorial design with these agronomic factors in both 0.76 and 0.51 m row widths was implemented for 13 trials in Illinois, United States, from 2014 to 2018. The agronomic treatments were compared to two controls: enhanced and standard, comprising all the factors applied at the enhanced or standard level, respectively. The 0.51 m enhanced management control yielded 3.3 Mg ha–1 (1.8–4.6 Mg ha–1 across the environments) more grain (25%) than the 0.76 m standard management control, demonstrating the apparent yield gap between traditional farm practices and attainable yield through enhanced agronomic management. Narrow rows and the combination of P-S-Zn and K-B fertility were the factors that provided the most significant yield increases over the standard control. Increasing plant population from 79,000 to 109,000 plants ha–1 reduced the yield gap when all other inputs were applied at the enhanced level. However, increasing plant population alone did not increase yield when no other factors were enhanced. Some agronomic factors, such as narrow rows and availability of plant nutrition, become more critical with increasing plant population when density-induced stress is more significant. Changes in yield were dependent upon changes in kernel number. Kernel weight was the heaviest when all the management factors were applied at the enhanced level while only planting 79,000 plants ha–1. Conversely, kernel weight was the lightest when increasing population to 109,000 plants ha–1 while all other factors were applied at the standard level. The yield contribution of each factor was generally greater when applied in combination with all other enhanced factors than when added individually to the standard input system. Additionally, the full value of high-input agronomic management was only realized when matched with greater plant density.

Summary: RNA binding protein (RBP) expression is finite. For RBPs that are vastly outnumbered by their potential target sites, a simple competition for binding can set the magnitude of post-transcriptional control. Here, we show that LIN28, best known for its direct regulation of let-7 miRNA biogenesis, is also indirectly regulated by its widespread binding of non-miRNA transcripts. Approximately 99% of LIN28 binding sites are found on non-miRNA transcripts, like protein coding and ribosomal RNAs. These sites are bound specifically and strongly, but they do not appear to mediate direct post-transcriptional regulation. Instead, non-miRNA sites act to sequester LIN28 protein and effectively change its functional availability, thus impeding the regulation of let-7 in cells. Together, these data show that the binding properties of the transcriptome broadly influence the ability of an RBP to mediate changes in RNA metabolism and gene expression.

Abstract Background Postoperative delirium is common in older adults, especially in those patients undergoing spine surgery, in whom it is estimated to occur in > 30% of patients. Although previously thought to be transient, it is now recognized that delirium is associated with both short- and long-term complications. Optimizing the depth of anesthesia may represent a modifiable strategy for delirium prevention. However, previous studies have generally not focused on reducing the depth of anesthesia beyond levels consistent with general anesthesia. Additionally, the results of prior studies have been conflicting. The primary aim of this study is to determine whether reduced depth of anesthesia using spinal anesthesia reduces the incidence of delirium after lumbar fusion surgery compared with general anesthesia. Methods This single-center randomized controlled trial is enrolling 218 older adults undergoing lumbar fusion surgery. Patients are randomized to reduced depth of anesthesia in the context of spinal anesthesia with targeted sedation using processed electroencephalogram monitoring versus general anesthesia without processed electroencephalogram monitoring. All patients are evaluated for delirium using the Confusion Assessment Method for 3 days after surgery or until discharge and undergo assessments of cognition, function, health-related quality of life, and pain at 3- and 12-months after surgery. The primary outcome is any occurrence of delirium. The main secondary outcome is change in the Mini-Mental Status Examination (or telephone equivalent) at 3-months after surgery. Discussion Delirium is an important complication after surgery in older adults. The results of this study will examine whether reduced depth of anesthesia using spinal anesthesia with targeted depth of sedation represents a modifiable intervention to reduce the incidence of delirium and other long-term outcomes. The results of this study will be presented at national meetings and published in peer-reviewed journals with the goal of improving perioperative outcomes for older adults. Trial registration Clinicaltrials.gov, NCT03133845. This study was submitted to Clinicaltrials.gov on October 23, 2015; however, it was not formally registered until April 28, 2017 due to formatting requirements from the registry, so the formal registration is retrospective.

Abstract Many RNA viruses have genetically diverse populations in a single host. Important biological characteristics may be related to the levels of diversity, including adaptability, host specificity, and host range. Shifting the virus between hosts might result in a change in the levels of diversity associated with the new host. The level of genetic diversity for these viruses is related to host, vector and virus interactions, and understanding these interactions may facilitate the prediction and prevention of emerging viral diseases. It is known that luteoviruses have a very specific interaction with aphid vectors. Previous studies suggested that there may be a tradeoff effect between the viral adaptation and aphid transmission when Soybean dwarf virus (SbDV) was transmitted into new plant hosts by aphid vectors. In this study, virus titers in different aphid vectors and the levels of population diversity of SbDV in different plant hosts were examined during multiple sequential aphid transmission assays. The diversity of SbDV populations revealed biases for particular types of substitutions and for regions of the genome that may incur mutations among different hosts. Our results suggest that the selection on SbDV in soybean was probably leading to reduced efficiency of virus recognition in the aphid which would inhibit movement of SbDV through vector tissues known to regulate the specificity relationship between aphid and virus in many systems.

Permafrost thaw poses a serious threat to the sustainable development of Arctic communities. Here the authors show that most fundamental Arctic infrastructure and population will be at high hazard risk, even if the Paris Agreement target is achieved.

Nitrogen (N) is an essential but generally limiting nutrient for biological systems. Development of the Haber-Bosch industrial process for ammonia synthesis helped to relieve N limitation of agricultural production, fueling the Green Revolution and reducing hunger. However, the massive use of industrial N fertilizer has doubled the N moving through the global N cycle with dramatic environmental consequences that threaten planetary health. Thus, there is an urgent need to reduce losses of reactive N from agriculture, while ensuring sufficient N inputs for food security. Here we review current knowledge related to N use efficiency (NUE) in agriculture and identify research opportunities in the areas of agronomy, plant breeding, biological N fixation (BNF), soil N cycling, and modeling to achieve responsible, sustainable use of N in agriculture. Amongst these opportunities, improved agricultural practices that synchronize crop N demand with soil N availability are low-hanging fruit. Crop breeding that targets root and shoot physiological processes will likely increase N uptake and utilization of soil N, while breeding for BNF effectiveness in legumes will enhance overall system NUE. Likewise, engineering of novel N-fixing symbioses in non-legumes could reduce the need for chemical fertilizers in agroecosystems but is a much longer-term goal. The use of simulation modeling to conceptualize the complex, interwoven processes that affect agroecosystem NUE, along with multi-objective optimization, will also accelerate NUE gains.