Accumulating evidence suggests that electroacupuncture (EA) has obevious therapeutic effects and unique advantages in alleviating myocardial ischemia-reperfusion injury (MIRI), while the underlying neuromolecular mechanisms of EA intervention for MIRI have not been fully elucidated. The aim of the study is to investigate the role of the neural pathway of hypothalamic paraventricular nucleus (PVN) neurons projecting to the rostral ventrolateral medulla (RVLM) in the alleviation of MIRI rats by EA preconditioning. MIRI models were established by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 2 h. Electrocardiogram recording, chemogenetics, enzyne-linked immunosorbent assay, multichannel physiology recording, hematoxylin-eosin and immunofluorescence staining methods were conducted to demonstrate that firing frequencies of neurons in the PVN and expression of c-Fos decreased by EA pretreatment. Meanwhile, EA preconditioning significantly reduced the levels of creatine kinase isoenzymes (CK-MB), cardiac troponin I (cTnI) and lactic dehydrogenase (LDH). Virus tracing showed a projection connection between PVN and RVLM. Inhibition of the PVN-RVLM neural pathway could replicate the protective effect of EA pretreatment on MIRI rats. However, activation of the pathway weakened the effect of EA preconditioning. EA pretreatment alleviated MIRI by regulating PVN neurons projecting to RVLM. This work provides novel evidence of EA pretreatment for improving MIRI.

Aim: The pharmacokinetics of doravirine have been studied in clinical trials, but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine pharmacokinetics (a CYP3A4 substrate) in real-world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared to a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. Conclusion: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected non-adherence or pregnancy.

Intraspecific variation in plants is expected to have profound impacts on the arthropod communities associated with them. Because sexual dimorphism in plants is expected to provide consistent variation among individuals of the same species, researchers have often studied the effect it has on associated arthropods. Nevertheless, most studies have focused on the effect of sexual dimorphism in a single or a few herbivores, thus overlooking the potential effects on the whole arthropod community. Our main objective was to evaluate effects of Buddleja cordata’s plant-sex on its associated arthropod community. We surveyed 13 pairs of male and female plants every two months during a year (June 2010-April 2011). Every sampling date, we measured plant traits (water content and leaf thickness), herbivory, and the arthropod community. We did not find differences in herbivory between plant sex or through time. However, we found differences in water content through time, with leaf water-content matching the environmental seasonality. For arthropod richness, we found 68 morphospecies associated with female and 72 with male plants, from which 53 were shared by both sexes. We did not observe differences in morphospecies richness; however, we found sex-associated differences in the diversity of all species and differences on the diversity of the most abundant species with an interesting temporal component. During peak flowering season male plants showed higher values on both parameters, but during the peak fructification season female plants showed the higher values on both diversity parameters. Our research exemplifies the interaction between plant-phenology and plant-sex as drivers of arthropod communities’ diversity, even when plant sexual-dimorphism is inconspicuous, and highlighting the importance of accounting for seasonal variation. We stress the need of conducting more studies that test this time-dependent framework in other dioecious systems, as it has the potential to reconcile previous contrasting observations reported in the literature.

Abstract Background and Purpose Pneumoconiosis, especially silicosis has emerged as a prominent occupational disease with remarkable global implications with no definitive cure available. While pirfenidone and nintedanib have been approved in treating idiopathic pulmonary fibrosis, their potential efficacy as anti-fibrotic agents in advanced silicosis warrants further investigation. Thus, we aimed to assess the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and further elucidate the underlying mechanisms involved in their therapeutic actions. Experimental Approach We administrated monotherapy or combination therapy of pirfenidone and nintedanib with low and high doses in silicosis mouse models established after 6 weeks and then evaluated lung function, inflammatory responses, and fibrotic status. Moreover, we employed transcriptomic and metabolomic analyses to unravel the mechanisms underlying different therapeutic strategies. Key Results Both pirfenidone and nintedanib were demonstrated to be effective for advanced silicosis, with superior outcomes when used in combination. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects through modulation of immune responses, signaling cascades, circadian rhythm, and metabolic processes of substances including lipid, amino acids, nucleotides, and carbohydrates. Conclusion and Implications In conclusion, pirfenidone and nintedanib, either administered individually or in combination, exhibit remarkable potential in advanced silicosis mouse models. Further, combined therapy outperformed monotherapy even at a half dose. These therapeutic benefits are attributed to their influence on diverse signaling pathways and metabolic processes. Keywords: silicosis, pulmonary fibrosis, pirfenidone, nintedanib, multi-omics.

Land degradation (LD) is a severe and well-known global concern. Therefore, this review aimed to find broader connections between LD and the Sustainable Development Goals (SDGs). This literature review aims to synthesize the definitions, processes, assessments, and challenges associated with LD. Furthermore, we developed a universally applicable and concise definition of LD that links a wide range of contexts and studies. Specifically, we categorized LD-related processes into physical, chemical, and biological processes and synthesized 20 methods/formulas used in the assessment of LD. Finally, we synthesized the most significant challenges in the context of the resolution of LD and provided corresponding recommendations. The review also Identified the main SDG targets that LD directly affects and the role that LD in relation to the SDGs. Overall, we expect this literature review to be a valuable resource for researchers and practitioners aiming to obtain a broad and comprehensive understanding of LD. These findings should facilitate sustainable and scientifically rooted use of land resources.

The engineering rockmass is often prone to compression, therefore how to establish a fracture criterion to reflect the rockmass compression failure is vital. Take the rockmass with one oblique crack for instance, the mechanical behavior of the oblique crack face closure and friction sliding under uniaxial compression is firstly analyzed, and then the Kolossoff-Muskhelishvilli stress function of the rockmass under uniaxial compression is established based on the complex stress functions. Next, the calculation methods of the stress intensity factor (SIF) K and three T-stress components at or near the crack tip considering three kinds of crack parameters (e.g. geometry parameter, friction strength parameter and deformation parameter) are obtained. Thirdly, the improved maximum tangential stress (MTS) criterion is obtained considering T-stress and three kinds of crack parameters. Finally, the relevant experiments done by other researchers are adopted to verify the improved MTS criterion. Meanwhile, the effect of γ, the crack normal stiffness kn and shear stiffness ks, and the crack friction coefficient f on the wing-crack initiation angle are discussed with the parametric sensitivity analysis.

Life is not a beach for those animals that survive in the rough ecological conditions found in marine sandy beaches—and yet, microscopic animals thrive on them. We explore the drivers for meiofaunal diversity in beaches by analysing taxonomic and functional patterns of 348 flatworm communities across 116 reflective beaches in the Western Mediterranean, totalling 152 species (61.2% new to Science). First, we confirm that species richness does not differ between beach hydrodynamic levels (swash, shoaling and surf) but rather depends on the characteristics of each beach. Second, we demonstrate that species composition across those levels depends on the species traits, in addition to geographical and abiotic factors. Third, we highlight that the species functional space has a lower richness than expected and a lower redundancy in the wave-exposed swash level compared to the shoaling and subtidal levels, suggesting a trait-based ecological filtering. Finally, we show that those differences depend on the higher frequency of hydrodynamics-related traits in the species of the swash level. Our results suggest that the rough hydrodynamic conditions in the swash level favour a unique combination of species traits, which might be linked to ecological speciation in flatworms but also in other interstitial animals.

Background: Transvenous leads have been implicated in tricuspid valve (TV) dysfunction, but limited data are available regarding the effect of extracting leads across the TV on valve regurgitation. Objective: The aim of this study is to quantify tricuspid regurgitation (TR) before and after lead extraction and identify predictors of worsening TR. Methods: We studied 321 patients who had echocardiographic data before and after lead extraction. TR was graded on a scale (0=none/trivial, 1=mild, 2=moderate, 3=severe). A change of > 1 grade following extraction was considered significant. Results: A total of 321 patients underwent extraction of a total of 338 leads across the TV (1.05 ± 0.31 leads across the TV per patient). There was no significant difference in average TR grade pre- and post-extraction (1.18 ± 0.91 vs. 1.15 ± 0.87; p=0.79). TR severity increased after extraction in 84 patients, but was classified as significantly worse (i.e. > 1 grade change in severity) in only 8 patients (2.5%). Use of laser lead extraction was associated with a higher rate of worsening TR post-extraction (44.0% vs. 31.6%, p=0.04). Conclusion: In our single-center analysis, extraction of leads across the TV did not significantly affect the extent of TR in most patients. Laser lead extraction was associated with a higher rate of worsening TR after extraction.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein (α-syn) accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. miR-221 is also implicated in promoting neuronal survival against oxidative stress and in promoting neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of this study; 1) miR-221 protects against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2) miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3) miR-221 has moderate predictive power for PD; 4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by manipulating the Akt signaling pathway, performs in controlling cell viability and apoptosis in PD. This review study suggests that miR-221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.

PREMISE OF THE STUDY Plant reproductive failure is a critical concern for conserving rare and endangered species that typically have low-density and sparse populations. One important factor contributing to reproductive failure is the spatial arrangement of plants within a population, which can lead to isolation and negatively affect seed output, particularly in obligate outcrossers. Additionally, this effect can be compounded by plant size. Here, we investigate how plants’ spatial distribution and size influence the reproductive success of Carica chilensis, a threatened papaya species. METHODS Using flower exclusion, we first examined whether C. chilensis can produce seeds via apomixis. We then used Spatial Point Pattern Analysis (SPPA) in three populations to examine the spatial arrangement of plants and, finally, we assess whether plant size and mate distance influence the reproductive success of this plant species. KEY RESULTS C. chilensis is a dioecious shrub unable to produce fruits through apomixis. The SPPA revealed significant clustering of female and male plants at different spatial scales, indicating a non-random distribution. Moreover, a significant attraction between the sexes suggested a preference for proximity. In two populations, closer proximity to male plants was linked to higher seed production. CONCLUSIONS Our study revealed that the absence of apomixis in C. chilensis makes it prone to experiencing distance-dependent reproductive failure. In particular, the seed set was compromised in female plants isolated from male neighbors. This link between isolation and seed production was especially significant in the driest site, and we discuss how environmental factors can exacerbate this effect.

Pseudocyesis is rare but it is a concern in remote areas based on sociocultural factors:

1. Graphs in research articles can increase the comprehension of statistical data but may mislead readers if poorly designed. Previous literature has found that the two most frequently used plot types - bar charts and dot and whisker plots - are a poor way to represent data because they only show the summary statistics of data, not their distribution, potentially hiding important information. 2. Calls have been made encouraging abandonment of bar charts and the use of more informative plot types, such as boxplots, violin plots, univariate scatter plots, and dot plots. We compare these plot types to assess their relative strengths and weaknesses to represent four different distributions of the data commonly observed in biological studies, finding that all the assessed plot types are either difficult to read at large sample sizes or misrepresent certain distributions of data. 3. We present an analysis of the plot types used in four ecology and conservation journals covering multiple areas of these research fields, finding widespread use of uninformative bar charts and dot and whisker plots (60 % of all plots showing one-dimensional data from multiple groups for the purpose of comparison). Some articles presented more informative figures by combining plot types, generally boxplots and a second layer such as a flat violin plot, to better display the data. This shows an appetite for more effective plot types within conservation and ecology, which may further increase if an accurate and user-friendly plot types were made available. 4. In response to this, we propose sea stack plots, which combine vertical histograms and summary statistics, and allow for an accurate representation of different data distributions, thereby largely overcoming the weaknesses associated with other alternatives to uninformative plots. We provide a tool to create sea stack plots with our R package ‘seastackplot’, available through GitHub.

Climate change affects biodiversity in diverse ways, necessitating the exploration of multiple climate dimensions using standardized metrics. However, existing methods for quantifying these metrics are scattered and tools for comparing alternative climate change metrics on the same footing are lacking. To address this gap, we developed “climetrics” which is an extensible and reproducible R package to spatially quantify and explore multiple dimensions of climate change through a unified procedure. Six widely used climate change metrics are currently implemented, including 1) Standardized Local Anomalies; 2) Changes in Probabilities of Local Climate Extremes; 3) Changes in Areas of Analogous Climates; 4) Novel Climates; 5) Changes in Distances to Analogous Climates; and 6) Climate Change Velocity. For climate change velocity, three different algorithms are implemented and available within the package including; a) Distanced-based Velocity (“dVe”); b) Threshold-based Velocity (“ve”); and c) Gradient-based Velocity (“gVe”). The package also provides additional tools to calculate the monthly mean of climate variables over multiple years, to quantify and map the temporal trend (slope) of a given climate variable at the pixel level, and to classify and map Köppen-Geiger (KG) climate zones. The climetrics R package is seamlessly integrated with the rts package for efficient handling of raster time-series data. The functions in climetrics are designed to be user-friendly, making them suitable for less-experienced R users. Detailed comments and descriptions in their help pages and vignettes of the package facilitate further customization by advanced users. In summary, the climetrics R package offers a unified framework for quantifying various climate change metrics, making it a useful tool for characterizing multiple dimensions of climate change and exploring their spatiotemporal patterns.

This paper investigates an optimal investment-reinsurance problem for an insurer who possesses extra information regarding the future realizations of the claim process and risky asset process. The insurer sells insurance contracts, has access to proportional reinsurance business, and invests in a financial market consisting of three assets: one risk-free asset, one bond and one stock. Here, the nominal interest rate is characterized by the Vasicek model; and the stock price is driven by the Heston’s stochastic volatility model. Applying the enlargement of filtration techniques, we establish the optimal control problem in which an insurer maximizes the expected power utility of the terminal wealth. By using the dynamic programming principle, the problem can be changed to four-dimensional Hamilton-Jacobi-Bellman equation. In addition, we adopt a deep neural network method by which the partial differential equation is converted to two backward stochastic differential equations and solved by a stochastic gradient descent-type optimization procedure. Numerical results obtained using TensorFlow in Python and the economic behavior of the approximate optimal strategy and the approximate optimal utility of the insurer are analyzed.

Background: Recent data found a correlation between lymphopenia occurring early during craniospinal irradiation (CSI) and risk of disease recurrence in newly-diagnosed childhood medulloblastoma. 1 However, the population included patients that received myelosuppressive chemotherapy prior to or during RT. Here we investigate the effect of lymphopenia during RT in patients with newly-diagnosed pediatric medulloblastoma who did not receive myelosuppressive chemotherapy with RT. Procedure: We analyzed 54 patients with newly-diagnosed medulloblastoma (ages 2-21 years) treated between 1997-2013 with CSI. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. Results: 78% of patients (40/51) had grade ≥3 lymphopenia by RT week 3; 49% (23/47) improved to grade ≤2 lymphopenia by week 5. Similarly, the lowest median absolute lymphocyte count (ALC) occurred during RT week 3. Sixteen of 54 (30%) patients recurred an average of 30.2 months post-diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during weeks 4 (log-rank p=0.015; Cox p=0.03) and 5 (log-rank p=0.0009; Cox p=0.004) of RT. Recurrence-free survival was lower in patients with ALC Conclusions: Lymphopenia during RT weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly-diagnosed medulloblastoma. Future studies should correlate baseline numbers of tumor-infiltrating lymphocytes with risks of lymphopenia during RT and tumor recurrence.

Root detritusphere, i.e., the soil in vicinity of decomposing root residues, plays an important role in soil microbial activity and C sequestration. Pore structure (size distributions and connectivity of soil pores) in the detritusphere serves as a major driver for these processes and, in turn, is influenced by physical characteristics of both soil and roots. This study compared pore structure characteristics in root detritusphere of soils of contrasting texture and mineralogy subjected to >6 years of contrasting vegetation: monoculture switchgrass and polyculture prairie systems. Soil samples were collected from five experimental sites in the US Midwest representing three soil types. Soil texture and mineralogy were measured using hydrometer and X-ray powder diffraction, respectively. The intact cores were scanned with X-ray computed micro-tomography to identify visible soil pores, biopores, and particulate organic matter (POM). We specifically focused on pore structure within the detritusphere around the POM of root origin. Results showed that detritusphere of coarser-textured soils, characterized by high sand and quartz contents, had lower porosity in the vicinity of POM compared to finer-textured soils. POM vicinities in finer soils had high proportions of large (>300 μm Ø) pores, and their pores were better connected than in coarser soils. Lower porosity in outer (>1 mm) parts of detritusphere of switchgrass than of prairie suggested soil compaction by roots, and the effect especially pronounced in coarser soils. The results demonstrated that soil texture and mineralogy played a major, while vegetation a more modest, role in defining the pore structure in root detritusphere.

Understanding the changes of sediment concentration (SC) in rivers is of great significance for correctly evaluating the effectiveness of soil and water conservation measures. By comparing the variation of SC in a typical watershed at the multi-year and the flood event scale, as well as the field investigations of sediment retained in check dams during a heavy rain in the Loess Hilly Area, the effect of check dams on SC were analyzed in this paper. Results showed that the check dam retained 56% of the eroded sediment in the watershed during the heavy rain on July 26, 2017, and greatly reduced the sediment transport to the downstream. Under the heavy rain condition, the slope measures (afforestation, grassing and terraces) had limited effect on reducing sediment yield, and can not stop the occurrence of hyperconcentrated flow. The average SC of runoff in the dam-controlled catchments was 438 kg/m 3, while it was only 148 kg/m 3 at the watershed outlet. The gully measures (check dams) played an important role in altering the characteristic of hyperconcentrated flow at the outlet of the watershed. In order to control the transport of hyperconcentrated flow to the downstream, more attention should be paid to the construction of check dams while carrying out vegetation ecological construction in the Loess Hilly Area.

Background: Ocular diseases, especially corneal diseases, are common in horses and their occurrence is associated with trauma. It is not known if management practices promote or prevent the development of ocular diseases, such as corneal ulcers. Objectives: This study aimed to evaluate how stable management practices, such as environment, feeding, or use of fly masks, are related to the development of eye diseases, primarily corneal ulceration, in horses. Study design: A survey of horse owners in the state of North Carolina was conducted which asked owners how they managed their horses and their responses were correlated to the types of eye diseases the horses experienced. Methods: Data collected from the survey included the primary environment of the horse (stable or pasture), type and method of feeding of hay, use of fly masks, and eye diseases that the horses have developed. Correlations between management practices and eye disease were then performed. Results: Of 446 horses, 161 (36% of total) had been diagnosed with a corneal ulcer, 44 (10%) had multiple corneal ulcers, 65 [15%] horses had uveitis, and 15 (3%) had immune-mediated keratitis. Horses that were kept in pasture exclusively were significantly less likely to have had a corneal ulcer than horses kept in a combination of pasture and stalls (p=0.0348). There were no significant correlations between types of hay or how hay was fed with the occurrence of corneal ulceration or other ocular diseases. Main limitations: Results, such as disease diagnoses, are solely based on horse owner responses and not medical professionals. Conclusions: Horses kept primarily in pasture have fewer ocular diseases, likely because they sustain less ocular trauma compared to horses kept in stables. How hay is fed does not correlate with the incidence of corneal or other ocular disease.