Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
Modulations of foveal vision associated with microsaccade preparation

Significance A tight relationship exists between eye movements and attention. Attention briefly shifts ahead of saccade execution, contributing to the processing of the saccade target before it lands in the high-resolution fovea. Yet, once the target is foveated, microsaccades, tiny saccades maintaining the fixated object within the foveal boundaries, continue to occur. The link between attention and microsaccades has been less investigated. Using high-precision eyetracking we examined whether and how foveal vision is affected by microsaccade preparation. Our findings show that during fixation foveal vision is modulated in a peculiar way both in space and in time. Right before microsaccade onset a surprisingly selective enhancement of high-acuity vision occurs at its target location. It is known that attention shifts prior to a saccade to start processing the saccade target before it lands in the foveola, the high-resolution region of the retina. Yet, once the target is foveated, microsaccades, tiny saccades maintaining the fixated object within the fovea, continue to occur. What is the link between these eye movements and attention? There is growing evidence that these eye movements are associated with covert shifts of attention in the visual periphery, when the attended stimuli are presented far from the center of gaze. Yet, microsaccades are primarily used to explore complex foveal stimuli and to optimize fine spatial vision in the foveola, suggesting that the influences of microsaccades on attention may predominantly impact vision at this scale. To address this question we tracked gaze position with high precision and briefly presented high-acuity stimuli at predefined foveal locations right before microsaccade execution. Our results show that visual discrimination changes prior to microsaccade onset. An enhancement occurs at the microsaccade target location. This modulation is highly selective and it is coupled with a drastic impairment at the opposite foveal location, just a few arcminutes away. This effect is strongest when stimuli are presented closer to the eye movement onset time. These findings reveal that the link between attention and microsaccades is deeper than previously thought, exerting its strongest effects within the foveola. As a result, during fixation, foveal vision is constantly being reshaped both in space and in time with the occurrence of microsaccades.
Immune responses and behavior alterations of Persian sturgeon fingerlings Acipenser persicus exposed to sublethal concentrations of diazinon

Diazinon is an organophosphate pesticide widely used in agricultural areas (especially paddy fields) in Iran. Similar to other pesticides, diazinon may enter aquatic systems due to run-off and affect various organisms living in rivers and estuaries. Persian sturgeon Acipenser persicus is one of the most economically important species in the Caspian Sea, which enters Iranian rivers, such as the Sefidroud River, for breeding. Fish eggs hatch in the river and fingerlings migrate to the sea after a period of time. The International Sturgeon Research Institute in Rasht, Iran, produces and releases millions of fingerling sturgeons into the coastal area of the Caspian Sea annually and the fingerlings may thus be affected by this pesticide. This study was carried out to determine sublethal effects of diazinon on some hematological indices of Persian sturgeon under lab conditions. Fish were exposed to concentrations of 0, 0.01, 1.095 (0.25 LC50), 2.19 (0.5 LC50) or 3.285 ppm (0.75 LC50) diazinon and responses were studied after 12, 24 and 96 h. After 12 h exposure, the fingerlings exposed to 2.19 and 3.285 ppm revealed a series of abnormal responses such as muscle paralysis, change in gills and abdominal color, erratic swimming, rapid operculum movement, and loss of body balance. The exposed sturgeons also exhibited a significantly lower number of erythrocyte (RBC) and leukocyte count (WBC) after 24 and 96 h exposure. Similarly, after 96 h, there was a significant decrease in hematocrit (Htc). Results also revealed a decrease in lymphocyte numbers and an increase of meta neutrophils, band neutrophils and total neutrophils after 24 and 96 h diazinon. Data suggest that diazinon affects physiological and hematological functions of A. persicus, which may finally affect survival of the fish. Diazinon concentration of 0.01 ppm has been recorded in water of the Sefidroud River, where about five million Persian sturgeon fries are released annually by the Iranian department of fishery hatcheries. Since this level of pesticide was found to be toxic for fish fries, it is critical to avoid any toxic impact by regular monitoring of diazinon levels in the river water.
Reshaping the Amyloid Buildup Curve in Alzheimer Disease? Partial-Volume Effect Correction of Longitudinal Amyloid PET Data

It was hypothesized that the brain β-amyloid buildup curve plateaus at an early symptomatic stage of Alzheimer disease (AD). Atrophy-related partial-volume effects (PVEs) degrade signal in hot-spot imaging techniques such as amyloid PET. The current study, a longitudinal analysis of amyloid-sensitive PET data, investigated the effect on the shape of the β-amyloid curve in AD when PVE correction (PVEC) is applied. Methods: We analyzed baseline and 2-y follow-up data for 216 symptomatic individuals on the AD continuum (positive amyloid status) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (17 with AD dementia and 199 with mild cognitive impairment), including 18F-florbetapir PET, MRI, and Mini Mental State Examination scores. For PVEC, the modified Müller–Gärtner method was performed. Results: Compared with non–PVE-corrected data, PVE-corrected data yielded significantly higher changes in regional and composite SUV ratio (SUVR) over time (P = 0.0002 for composite SUVRs). Longitudinal SUVR changes in relation to Mini Mental State Examination decreases showed a significantly higher slope for the regression line in the PVE-corrected than in the non–PVE-corrected PET data (F1 = 7.1, P = 0.008). Conclusion: These PVEC results indicate that the β-amyloid buildup curve does not plateau at an early symptomatic disease stage. A further evaluation of the impact of PVEC on the in vivo characterization of time-dependent AD pathology, including the reliable assessment and comparison of other amyloid tracers, is warranted.
Tree diversity effects through a temporal lens: implications for the abundance, diversity, and stability of foraging birds.

1. Tree diversity can exert a strong influence on consumers, but most studies have involved short-term assessments. Consequently, we have a limited understanding of temporal variation in the effects of tree diversity on multi-trophic communities and thus how tree diversity impacts ecological function. 2. We conducted a year-long study in an experimental system in southern Mexico assessing the effects of tree diversity on the abundance and diversity of visiting birds. To this end, we recorded bird visitation patterns for 32 plots (21 × 21 m; 12 monocultures, 20 four-species polycultures) every 45 days (n = 8 surveys) and for each plot estimated bird abundance, richness, functional diversity (FD), and phylogenetic diversity (PD). In each case, we reported temporal (intra-annual) variation in the magnitude of such diversity effects, and calculated the temporal stability of these bird responses. 3. Across surveys, tree diversity noticeably affected bird responses, demonstrated by significantly higher abundance (43%), richness (32%), PD (25%), and FD (25%) of birds visiting polyculture plots compared to monoculture plots, as well as a distinct species composition between plot types. We also found some degree of intra-annual variation in diversity effects on these response variables, ranging from surveys for which the tree diversity effect was not significant to surveys where a significant 80% increase (e.g. bird FD and PD) was observed in polyculture relative to monoculture plots. Notably, tree diversity increased the stability of all bird responses, with polycultures having a greater stability abundance (18%), richness (38%), PD (34%), and FD (32%) of birds visiting polycultures compared to monocultures. 4. These findings show that tree diversity not only increases bird visitation to plots, but also stabilizes bird habitat usage over time in ways that could lead to insurance-related mechanisms. These results are highly relevant for understanding the long-term effects of plant diversity on vertebrates and the persistence of bird-related ecosystem functions. Accordingly, more work is needed to unveil the ecological mechanisms underlying temporal variation in vertebrate responses to tree diversity and their consequences for community structure and function.
Reliable Road Scene Interpretation Based on ITOM with the Integrated Fusion of Vehicle and Lane Tracker in Dense Traffic Situation

Lane detection and tracking in a complex road environment is one of the most important research areas in highly automated driving systems. Studies on lane detection cover a variety of difficulties, such as shadowy situations, dimmed lane painting, and obstacles that prohibit lane feature detection. There are several hard cases in which lane candidate features are not easily extracted from image frames captured by a driving vehicle. We have carefully selected typical scenarios in which the extraction of lane candidate features can be easily corrupted by road vehicles and road markers that lead to degradations in the understanding of road scenes, resulting in difficult decision making. We have introduced two main contributions to the interpretation of road scenes in dense traffic environments. First, to obtain robust road scene understanding, we have designed a novel framework combining a lane tracker method integrated with a camera and a radar forward vehicle tracker system, which is especially useful in dense traffic situations. We have introduced an image template occupancy matching method with the integrated vehicle tracker that makes it possible to avoid extracting irrelevant lane features caused by forward target vehicles and road markers. Second, we present a robust multi-lane detection by a tracking algorithm that incudes adjacent lanes as well as ego lanes. We verify a comprehensive experimental evaluation with a real dataset comprised of problematic road scenarios. Experimental result shows that the proposed method is very reliable for multi-lane detection at the presented difficult situations.
Alleviation of Seed Dormancy in Spergularia marina

Spergularia marina seeds remain dormant under a number of environmental conditions. Apparently, the inability of this species to germinate is environmentally controlled, because exposure to light, cold stratification, or alternating day/night temperatures all play a role in breaking dormancy. Seeds were also inhibited from germinating at low temperatures or high salt concentrations. These enforced dormancies could be broken by eliminating the stress conditions Gibberellic acid treatments overcame dormancies induced by suboptimal environmental conditions.
Functional cycle of EEA1-positive early endosome: Direct evidence for pre-existing compartment of degradative pathway

Early endosomes, regarded as the main sorting station on endocytic pathway, are characterized by high frequency of homotypic fusions mediated by tethering protein EEA1. Despite intensive investigations, biogenesis of endosomes, boundaries between early and late endosomes, and process of cargo transition though them remain obscure. Here, using EGF/EGFR endocytosis as a model and confocal microscopy of fixed and live cells, we provide evidence favoring EEA1-vesicles being pre-existed vesicular compartment, that maintains its resident proteins’ level and is sensitive to biosynthetic, but not endocytic pathway disturbance. EEA1-vesicles directly fuse with incoming EGF/EGFR-vesicles into hybrid endosomes with separated EEA1- and EGFR-domains, thus providing a platform for rapid achievement of an excess of surface-derived membrane that is used to form intraluminal vesicles (ILVs). Thus, multivesicular structures colocalized with EEA1 are still early endosomes. “EEA1-cycle” ends by exclusion of EGFR-containing domains with ILVs inside that turns into MVE and restoration of initial EEA1-vesicles population.
A conformation-based intra-molecular initiation factor identified in the flavivirus RNA-dependent RNA polymerase

The flaviviruses pose serious threats to human health. Being a natural fusion of a methyltransferase (MTase) and an RNA-dependent RNA polymerase (RdRP), NS5 is the most conserved flavivirus protein and an important antiviral target. Previously reported NS5 structures represented by those from the Japanese encephalitis virus (JEV) and Dengue virus serotype 3 (DENV3) exhibit two apparently different global conformations, defining two sets of intra-molecular MTase-RdRP interactions. However, whether these NS5 conformations are conserved in flaviviruses and their specific functions remain elusive. Here we report two forms of DENV serotype 2 (DENV2) NS5 crystal structures representing two conformational states with defined analogies to the JEV-mode and DENV3-mode conformations, respectively, demonstrating the conservation of both conformation modes and providing clues for how different conformational states may be interconnected. Data from in vitro polymerase assays further demonstrate that perturbing the JEV-mode but not the DENV3-mode intra-molecular interactions inhibits catalysis only at initiation, while the cell-based virological analysis suggests that both modes of interactions are important for virus proliferation. Our work highlights the role of MTase as a unique intra-molecular initiation factor specifically only through the JEV-mode conformation, providing an example of conformation-based crosstalk between naturally fused protein functional modules.
LMX1B rs10733682 Polymorphism Interacts with Macronutrients, Dietary Patterns on the Risk of Obesity in Han Chinese Girls

Previous studies have found that LMX1B rs10733682 polymorphism is associated with Body Mass Index (BMI) in European and American Indian adults. In this study, the association of rs10733682 polymorphism with obesity-related indicators, and its interaction with macronutrients and dietary patterns (DPs) were explored in Chinese children (n = 798). The rs10733682 polymorphism was genotyped by improved Multiple Ligase Detection Reaction (iMLDR). Four DPs were identified by factor analysis. The AA genotype had a higher incidence of overweight/obesity than GG+GA genotypes (P = 0.010) in girls (n = 398), but no difference in boys. The AA genotype in girls could interact with intake of energy, fat and carbohydrate, causing an increased triglyceride (TG), (P = 0.021, 0.003, 0.002, respectively), and also could interact with energy from protein, causing an elevated BMI (P = 0.023) and waist (P = 0.019). Girls inclining to the HED (high-energy density)-DP were associated with increased TG (P = 0.033), and girls inclining to the VEF (vegetables, eggs, and fishes based)-DP were associated with decreased total cholesterol (TC, P = 0.045) and decreased low density lipoprotein cholesterin (LDL, P = 0.016). The findings indicated that the AA genotype of rs10733682 and the HED-DP are potential risk factors of obesity in Chinese girls.
Patient Accessibility and Budget Impact of Orphan Drugs in South Korea: Long-Term and Real-World Data Analysis (2007–2019)

This study aimed to identify orphan drug accessibility and impact on pharmaceutical budgets in South Korea by analyzing the status of orphan drug designation, approval, reimbursement, and pharmaceutical expenditure. We analyzed the dataset on orphan drugs designated, approved, and reimbursed from 2007 to 2019 based on long-term real-world data. The designated and approved orphan drugs were 165 and 156, respectively, and 88 out of 156 approved products were reimbursed. Total expenditure on orphan drugs increased annually to account for about 1.44% of total pharmaceutical expenditure in 2018. Orphan drug expenditure per patient increased on average by 8.7% per year. The average annual cost of orphan drugs was USD 27,000–USD 47,000, with the maximum value of USD 260,000–USD 560,000. As there are a number of orphan drugs that have not yet been reimbursable after approval, a reimbursement policy should be established that considers the characteristics of orphan drugs. Since the rapid increase in orphan drug expenditure can be a potential threat to the insurance budget, budget management should also be considered. In conclusion, it is necessary to take preemptive measures to manage the health insurance budget efficiently while improving patient accessibility to orphan drugs.
Taxonomic resolution of benthic macroinvertebrate communities in bioassessments

BRIDGES is a recurring feature of J-NABS intended to provide a forum for the interchange of ideas and information between basic and applied researchers in benthic science. Articles in this series focus on topical research areas and linkages between basic and applied aspects of research, monitoring, policy, and education. Readers with ideas for topics should contact Associate Editors, Nick Aumen and Marty Gurtz. The issue of taxonomic resolution has been a topic of interest in benthological studies for a long time, but the increasing use of aquatic insects—and more recently algae—in assessing water quality has heightened the importance of understanding the tradeoffs associated with different levels of taxonomy. Bailey and co-authors lead off this set of papers with a review of the types of studies and questions for which species identifications are essential, but then examine whether there are circumstances—e.g., in some bioassessments—in which taxonomic information at a higher (e.g., family) level is sufficient, or may even be better. They propose a 2-tiered approach for taxonomy used in bioassessment studies: family-level identifications for multivariate analyses or index calculation, and species identification for a short list of indicator taxa that are appropriate for a particular study. Lenat and Resh review a variety of uses of taxonomic information for aquatic insects and recommend levels of taxonomy that are appropriate for different situations. They conclude that biological monitoring studies yield the greatest benefits using genus- or species-level taxonomy. Hill et al. examine issues of taxonomic resolution for diatom studies, using results from a large set of diatom assemblage data collected from 199 streams over a 3-y period. They found that genus-level taxonomy appears to adequately describe the response of some diatom assemblage attributes to environmental gradients, especially for those gradients that involve morphological (motility) or physiological (pH tolerance) adaptations that are related to evolved genus-level characteristics. Nick Aumen, nick_aumen@nps.gov Marty Gurtz, megurtz@usgs.gov Co-editors
The effect of organic matter accumulation on phosphorus release in sediment of Chinese shallow lakes.

The effects of organic matter in sediment on phosphorus release were studied by field investigations in eight Chinese shallow freshwater lakes with different trophic status and a laboratory experiment. The sediment organic matter content paralleled the trophic status, ranging from 6.1 to 173.0 g kg(-1) (dry weight), with the mean value of 63.1 g kg(-1) (dry weight). It was positively proportional to Soluble reactive phosphorus concentration in the interstitial water in a form of exponential function, but inversely related to the sediment Fe/P ratio. The sediment alkaline phosphatase activity was significantly related not only to the organic matter content (r = 0.829, P < 0.01, n = 120), but also to the soluble reactive phosphorus concentration in interstitial water (r = 0.454, P < 0.01, n = 42). In the laboratory experiment, the addition of organic matter (dry materials of an aquatic macrophyte) into the sediment significantly enhanced alkaline phosphatase activity and soluble reactive phosphorus release. However, in the treatment with organic matter added and aeration, this release was generally prevented in spite of an increase in APA. Hence, sediment organic matter can effectively accelerate phosphorus release by enzymatic hydrolysis and anaerobic desorption. The latter mechanism seems to be more important.
Corn silage with and without enzyme-bacteria inoculants on performance, carcass characteristics and meat quality in feedlot finished crossbred bulls

Two height cuttings of corn silage with or without enzyme inoculants were evaluated for 68 days on performance, carcass characteristics, meat quality and chemical composition of the Longissimus muscle in crossbred bulls (F1 - ½ Nellore vs. ½ Angus) finished in feedlot. Thirty-two 20-month-old bulls, with initial average weight of 374±25 kg, were kept in individual pens (10 m2). Diets consisted of 50% roughage and 50% concentrate, with an expected 1.80 kg/day weight gain. The experimental design with four diets and eight replications was completely randomized. Different cutting heights, low (25 cm) and high (45 cm), with or without enzyme inoculants, were studied. Live weight, average daily gain, feed intake, feed efficiency, carcass characteristics, muscle, fat and bone percentages at the 11th and 12th ribs, chemical composition of the Longissimus muscle, sum of saturated, mono-unsaturated, poly-unsaturated fatty acids, n-3 fatty acids, n-6 fatty acids, and the poly-unsaturated:saturated and n-6:n-3 relations were determined. Cutting height of silage corn and the use of inoculants did not affect final live weight, average daily gain, feed intake, alimentary efficiency of dry matter, carcass characteristics, meat quality, chemical composition of the Longissimus muscle or fatty acid profile. High cutting of silage corn (45 cm above the ground) and the use of inoculants are not necessary in the case of cattle finished in feedlot, with 1.8 kg daily gain.