Distinct Effects Research Articles

Analysis of the Dynamic Mechanical Properties and Energy Dissipation of Water-Saturated Fissured Sandstone Specimens

To investigate the dynamic mechanical properties of water-saturated fissure rock at different strain rates, prefabricated sandstone specimens with a 45° dip angle were treated with water saturation and the impact compression test was performed with a Split Hopkinson Pressure Bar (SHPB) test device at different impact pressures. The results show that the clusters of dynamic stress–strain curves of water-saturated and natural sandstone specimens with a 45° dip angle of prefabricated fissures are basically similar under different impact air pressures. A distinct strain rate effect was observed for dynamic strain and dynamic compressive strength, both of which increased with increasing strain rate. From the failure pattern of the specimen, it can be seen that cracks appeared from the tip of the prefabricated fissure under axial stress, spreading to both ends and forming wing cracks and anti-wing cracks associated with shear cracks. As the strain rate increased, the energy dissipation density of the specimen gradually increased, and the macroscopic cracks cross-expanded with each other. The fracture form of the specimen showed a small block distribution, and the average particle size of the specimen gradually decreased. The specimen crushing energy dissipation density was negatively correlated with fracture size, reflecting a certain rate correlation. The sandstone fragments’ fractal dimension increases with the increase in crushing energy dissipation density, and the fractal dimension may be applied as a quantitative index to characterize sandstone crushing.

Type 2M/2A von Willebrand disease: a shared phenotype between type 2M and 2A

AbstractFour variants have been continuously subjected to debate and received different von Willebrand disease (VWD) classifications: p.R1315L, p.R1315C, p.R1374H, and p.R1374C. We chose to comprehensively investigate these variants with full set of VWD tests, protein-modeling predictions and applying structural biology. Patients with p.R1315L, p.R1315C, p.R1374H, and p.R1374C were included. A group with type 2A and 2M was included to better understand similarities and differences. Patients were investigated for phenotypic assays and underlying disease mechanisms. We applied deep protein modeling predictions and structural biology to elucidate the causative effects of variants. Forty-three patients with these variants and 70 with 2A (n = 35) or 2M (n = 35) were studied. Patients with p.R1315L, p.R1374H, or p.R1374C showed a common phenotype between 2M and 2A using von Willebrand factor (VWF):GPIbR/VWF:Ag and VWF:CB/VWF:Ag ratios and VWF multimeric profile, whereas p.R1315C represented a type 2M phenotype. There was an overall reduced VWF synthesis or secretion in 2M and cases with p.R1315L, p.R1374H, and p.R1374C, but not in 2A. Reduced VWF survival was observed in most 2A (77%), 2M (80%), and all 40 cases with p.R1315L, p.R1374H, and p.R1374C. These were the only variants that fall at the interface between the A1-A2 domains. p.R1315L/C mutants induce more compactness and internal mobility, whereas p.R1374H/C display a more extended overall geometry. We propose a new classification of type 2M/2A for p.R1315L, p.R1374H, and p.R1374C because they share a common phenotype with 2M and 2A. Our structural analysis shows the unique location of these variants on the A1-A2 domains and their distinctive effect on VWF.

Land leveling and cover cropping impacts on chemical and biological properties of paddy soil

Aim of study: To examine the impact of solitary land leveling and its combination with cover cropping on the chemical and biological characteristics of paddy soil. Area of study: This research focused on paddy fields located in Guilan Province, situated in northern Iran. Specifically, two sites were chosen for investigation, where land leveling had been conducted 5 years and 2 years prior to this study, respectively. Furthermore, cover cropping was implemented during the second year after the latter area's land leveling. Material and methods: A total of 80 composite soil samples were collected, with 20 samples gathered from both leveled and unleveled plots at the designated study sites. Various soil chemical and biological properties such as organic carbon, total nitrogen, available phosphorus, exchangeable potassium, microbial respiration, and biomass carbon were quantified. Subsequently, a paired t-test was employed to analyze the impact of land leveling and the combined effects of land leveling with cover cropping on soil attributes. Main results: The study revealed that five years after land leveling, there was a significant decrease in organic carbon, total nitrogen, microbial respiration, and biomass carbon. In contrast, the area leveled and cover cropped for two years exhibited higher levels of these attributes compared to adjacent unleveled parcels. Research highlights: This study highlights the distinct effects that solitary land leveling and land leveling combined with sustainable practices like cover cropping have on soil attributes.

PMP2 regulates myelin thickening and ATP production during remyelination.

It is well established that axonal Neuregulin 1 type 3 (NRG1t3) regulates developmental myelin formation as well as EGR2-dependent gene activation and lipid synthesis. However, in peripheral neuropathy disease context, elevated axonal NRG1t3 improves remyelination and myelin sheath thickness without increasing Egr2 expression or activity, and without affecting the transcriptional activity of canonical myelination genes. Surprisingly, Pmp2, encoding for a myelin fatty acid binding protein, is the only gene whose expression increases in Schwann cells following overexpression of axonal NRG1t3. Here, we demonstrate PMP2 expression is directly regulated by NRG1t3 active form, following proteolytic cleavage. Then, using a transgenic mouse model overexpressing axonal NRG1t3 (NRG1t3OE) and knocked out for PMP2, we demonstrate that PMP2 is required for NRG1t3-mediated remyelination. We demonstrate that the sustained expression of Pmp2 in NRG1t3OE mice enhances the fatty acid uptake in sciatic nerve fibers and the mitochondrial ATP production in Schwann cells. In sum, our findings demonstrate that PMP2 is a direct downstream mediator of NRG1t3 and that the modulation of PMP2 downstream NRG1t3 activation has distinct effects on Schwann cell function during developmental myelination and remyelination.

Sleep deprivation detected by voice analysis.

Sleep deprivation has an ever-increasing impact on individuals and societies. Yet, to date, there is no quick and objective test for sleep deprivation. Here, we used automated acoustic analyses of the voice to detect sleep deprivation. Building on current machine-learning approaches, we focused on interpretability by introducing two novel ideas: the use of a fully generic auditory representation as input feature space, combined with an interpretation technique based on reverse correlation. The auditory representation consisted of a spectro-temporal modulation analysis derived from neurophysiology. The interpretation method aimed to reveal the regions of the auditory representation that supported the classifiers' decisions. Results showed that generic auditory features could be used to detect sleep deprivation successfully, with an accuracy comparable to state-of-the-art speech features. Furthermore, the interpretation revealed two distinct effects of sleep deprivation on the voice: changes in slow temporal modulations related to prosody and changes in spectral features related to voice quality. Importantly, the relative balance of the two effects varied widely across individuals, even though the amount of sleep deprivation was controlled, thus confirming the need to characterize sleep deprivation at the individual level. Moreover, while the prosody factor correlated with subjective sleepiness reports, the voice quality factor did not, consistent with the presence of both explicit and implicit consequences of sleep deprivation. Overall, the findings show that individual effects of sleep deprivation may be observed in vocal biomarkers. Future investigations correlating such markers with objective physiological measures of sleep deprivation could enable "sleep stethoscopes" for the cost-effective diagnosis of the individual effects of sleep deprivation.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Venom Composition of Neglected Bothropoid Snakes from the Amazon Rainforest: Ecological and Toxinological Implications.

Snake venoms have evolved in several families of Caenophidae, and their toxins have been assumed to be biochemical weapons with a role as a trophic adaptation. However, it remains unclear how venom contributes to the success of venomous species for adaptation to different environments. Here we compared the venoms from Bothrocophias hyoprora, Bothrops taeniatus, Bothrops bilineatus smaragdinus, Bothrops brazili, and Bothrops atrox collected in the Amazon Rainforest, aiming to understand the ecological and toxinological consequences of venom composition. Transcriptomic and proteomic analyses indicated that the venoms presented the same toxin groups characteristic from bothropoids, but with distinct isoforms with variable qualitative and quantitative abundances, contributing to distinct enzymatic and toxic effects. Despite the particularities of each venom, commercial Bothrops antivenom recognized the venom components and neutralized the lethality of all species. No clear features could be observed between venoms from arboreal and terrestrial habitats, nor in the dispersion of the species throughout the Amazon habitats, supporting the notion that venom composition may not shape the ecological or toxinological characteristics of these snake species and that other factors influence their foraging or dispersal in different ecological niches.

Cumulative Genetic Scores Interact with Maternal and Paternal Parenting in Predicting Parent-Adolescent Cohesion and Conflict.

Previous research concerning the interplay between genetics and parenting in the development of the parent-child relationship during adolescence has been extremely scarce, predominantly adopting single-gene designs. This limited body of work has largely overlooked the distinct effects of maternal and paternal roles, as well as potential gender differences. Additionally, existing gene-by-environment (G × E) studies have mainly concentrated on adverse environmental factors and associated negative outcomes, somewhat neglecting positive environments and outcomes. The present study examined the interactions of cumulative genetic scores (CGS, dopamine receptor D2 TaqIA and oxytocin receptor gene rs53576 polymorphisms) with both positive and negative parenting on parent-adolescent cohesion and conflict. Furthermore, this study aimed to ascertain with which gene-environment model the potential G × E interactions would align. A total of 745 Chinese Han adolescents (Mage = 13.36 ± 0.96 years; 46.8% girls) from grades 7 to 9 participated in this study. Results revealed a significant effect of CGS and negative maternal parenting on mother-adolescent conflict among males, consistent with the weak differential susceptibility model. As CGS increased, the effects of negative maternal parenting on mother-son conflict were magnified. These findings have implications for the timing and focus of interventions aimed at improving parent-adolescent relationships.

Differential regulations of neural activity and survival in primary cortical neurons by PFOA or PFHpA

Perfluorinated compounds (PFCs), organofluoride compounds comprising carbon–fluorine and carbon–carbon bonds, are used as water and oil repellents in textiles and pharmaceutical tablets; however, they are associated with potential neurotoxic effects. Moreover, the impact of PFCs on neuronal survival, activity, and regulation within the brain remains unclear. Additionally, the mechanisms through which PFCs induce neuronal toxicity are not well-understood because of the paucity of data. This study elucidates that perfluorooctanoic acid (PFOA) and perfluoroheptanoic acid (PFHpA) exert differential effects on the survival and activity of primary cortical neurons. Although PFOA triggers apoptosis in cortical neurons, PFHpA does not exhibit this effect. Instead, PFHpA modifies dendritic spine morphogenesis and synapse formation in primary cortical neuronal cultures, additionally enhancing neural activity and synaptic transmission. This research uncovers a novel mechanism through which PFCs (PFHpA and PFOA) cause distinct alterations in dendritic spine morphogenesis and synaptic activity, shedding light on the molecular basis for the atypical behaviors noted following PFC exposure. Understanding the distinct effects of PFHpA and PFOA could guide regulatory policies on PFC usage and inform clinical approaches to mitigate their neurotoxic effects, especially in vulnerable population.

Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in Streptococcus pneumoniae.

Streptococcus pneumoniae (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This study explores the intriguing role of polyamines, ubiquitous, small organic cations, in modulating virulence factors, especially the capsule, a crucial determinant of Spn's pathogenicity. Using chemical inhibitors, difluoromethylornithine (DFMO) and AMXT 1501, this research unveils distinct regulatory effects on the gene expression of the Spn D39 serotype in response to altered polyamine homeostasis. DFMO inhibits polyamine biosynthesis, disrupting pathways associated with glucose import and the interconversion of sugars. In contrast, AMXT 1501, targeting polyamine transport, enhances the expression of polyamine and glucose biosynthesis genes, presenting a novel avenue for regulating the capsule independent of glucose availability. Despite ample glucose availability, AMXT 1501 treatment downregulates the glycolytic pathway, fatty acid synthesis, and ATP synthase, crucial for energy production, while upregulating two-component systems responsible for stress management. This suggests a potential shutdown of energy production and capsule biosynthesis, redirecting resources towards stress management. Following DFMO and AMXT 1501 treatments, countermeasures, such as upregulation of stress response genes and ribosomal protein, were observed but appear to be insufficient to overcome the deleterious effects on capsule production. This study highlights the complexity of polyamine-mediated regulation in S. pneumoniae, particularly capsule biosynthesis. Our findings offer valuable insights into potential therapeutic targets for modulating capsules in a polyamine-dependent manner, a promising avenue for intervention against S. pneumoniae infections.

Pathogenic variants in CRX have distinct cis-regulatory effects on enhancers and silencers in photoreceptors.

Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox (CRX) are linked with human blinding diseases that vary in their severity and age of onset. How different variants in this single TF alter its function in ways that lead to a range of phenotypes is unclear. We characterized the effects of human disease-causing variants on CRX cis-regulatory function by deploying massively parallel reporter assays (MPRAs) in mouse retina explants carrying knock-ins of two variants, one in the DNA-binding domain (p.R90W) and the other in the transcriptional effector domain (p.E168d2). The degree of reporter gene dysregulation in these mutant Crx retinas corresponds with their phenotypic severity. The two variants affect similar sets of enhancers, and p.E168d2 has distinct effects on silencers. Cis-regulatory elements (CREs) near cone photoreceptor genes are enriched for silencers that are derepressed in the presence of p.E168d2. Chromatin environments of CRX-bound loci are partially predictive of episomal MPRA activity, and distal elements whose accessibility increases later in retinal development are enriched for CREs with silencer activity. We identified a set of potentially pleiotropic regulatory elements that convert from silencers to enhancers in retinas that lack a functional CRX effector domain. Our findings show that phenotypically distinct variants in different domains of CRX have partially overlapping effects on its cis-regulatory function, leading to misregulation of similar sets of enhancers while having a qualitatively different impact on silencers.

Anaphylactic shock following the mad honey consumption: a case report

Introduction: Mad honey consumption is a common practice in Nepal for medicinal and consumption purposes, but it can lead to severe adverse effects. Grayanotoxin I and Grayanotoxin III isoforms found in rhododendron interfere with voltage-gated sodium channels resulting in gastrointestinal symptoms, and cardiovascular effects such as low blood pressure, abnormal heart rhythms, cardiac arrest, and abnormal electrical conduction in the heart, as well as rare central nervous system disorders. Here the authors report a case of Mad honey consumption leading to anaphylactic shock along with its investigations and management. Case presentation: The authors present a case of a 51-year-old female who developed anaphylactic shock after consuming mad honey. The patient experienced symptoms including nausea, vomiting, abdominal pain, sweating, dizziness, facial and lip swelling, but no chest pain, loss of consciousness, abnormal body movement, or dyspnoea. The patient had no prior medical conditions, regular medications, or history of allergic reactions to honey or pollen. Discussion: Mad honey intoxication is caused by grayanotoxins, with distinct cardiac effects for different types of grayanotoxins. Symptoms include bradycardia, hypotension, abdominal pain, dizziness, and nausea, which subsided within 24 h following the initial management. The presence of grayanotoxin can be detected using specialized instrumentation, but it may not be available in all medical facilities. Co-intoxication with alcohol or propolis may also occur. Conclusion: This case highlights the importance of recognizing and managing complications associated with mad honey consumption, particularly in regions where it is prevalent. Prompt medical attention is advised if unusual symptoms occur after honey consumption.

Tet-mediated DNA methylation dynamics affect chromosome organization.

DNA Methylation is a significant epigenetic modification that can modulate chromosome states, but its role in orchestrating chromosome organization has not been well elucidated. Here we systematically assessed the effects of DNA Methylation on chromosome organization with a multi-omics strategy to capture DNA Methylation and high-order chromosome interaction simultaneously on mouse embryonic stem cells with DNA methylation dioxygenase Tet triple knock-out (Tet-TKO). Globally, upon Tet-TKO, we observed weakened compartmentalization, corresponding to decreased methylation differences between CpG island (CGI) rich and poor domains. Tet-TKO could also induce hypermethylation for the CTCF binding peaks in TAD boundaries and chromatin loop anchors. Accordingly, CTCF peak generally weakened upon Tet-TKO, which results in weakened TAD structure and depletion of long-range chromatin loops. Genes that lost enhancer-promoter looping upon Tet-TKO showed DNA hypermethylation in their gene bodies, which may compensate for the disruption of gene expression. We also observed distinct effects of Tet1 and Tet2 on chromatin organization and increased DNA methylation correlation on spatially interacted fragments upon Tet inactivation. Our work showed the broad effects of Tet inactivation and DNA methylation dynamics on chromosome organization.

Effects of concentric and eccentric cycling training on muscular hemodynamic and erythrocyte rheological responses to exercise in sedentary males

AbstractErythrocyte rheological properties contribute to the dynamic regulation of vascular resistance to flow shear force, facilitating blood delivery from the heart to peripheral tissues. Despite improved physical performance, the effects of eccentric cycling training (ECT) on erythrocyte rheological characteristics remain unclear. This study investigates the distinct effects of ECT and concentric cycling training (CCT) on muscular hemodynamic and erythrocyte rheological responses to exercise. Thirty‐nine sedentary healthy males were randomly assigned to either ECT (n = 13) or CCT (n = 13) at 45%–70% of the maximal workload for 30 min/day, 5 days/week for 6 weeks, or to a control group (n = 13) that did not receive any exercise intervention. A graded exercise test (GXT) was performed before and after the intervention. Muscular hemodynamic and erythrocyte rheological responses to the GXT were determined by near‐infrared spectroscopy and ektacytometry, respectively. Both ECT and CCT significantly enhanced perfusion (Δ[THb]VL) and O2 extraction (Δ[HHb]VL) in vastus lateralis during GXT. Before training, an acute GXT significantly reduced erythrocyte deformability and increased aggregability, whereas after 6 weeks of either ECT or CCT, the extent of erythrocyte rheological changes caused by GXT was diminished. Moreover, CCT elicited higher improvements in cardiac output (CO), VO2, and work‐rate at peak performance than ECT. In hierarchical regression, the change of maximal CO was the most influential factor affecting VO2max following CCT. In contrast, enhanced VO2max was significantly associated with Δ[HHb]VL and erythrocyte aggregability/deformability in ECT. Although CCT is superior to ECT for increasing aerobic capacity, either ECT or CCT effectively enhances aerobic efficiency by improving muscular hemodynamic and erythrocyte rheological responses to exercise.

Wnt10b knockdown regulates the relative balance of adipose tissue-resident T cells and inhibits white fat deposition.

Wnt10b is one of critical Wnt family members that being involved in networks controlling stemness, pluripotency and cell fate decisions. However, its role in adipose-resident T lymphocytes and further in fat metabolism yet remains largely unknown. In the present study, we demonstrated a distinctive effect for Wnt10b on the relative balance of T lymphocytes in adipose tissue by using a Wnt10b knockdown mouse model. Wnt10b knockdown led to a reduction of adipose-resident CD4+ T cells and an elevation of Foxp3+/CD4+ Treg cells. Wnt10b-knockdown mice fed with standard diet showed less white fat deposition owing to the suppressed adipogenic process. Moreover, under high fat diet conditions, Wnt10b knockdown resulted in an alleviated obesity symptoms, as well as an improvement of glucose homeostasis and hepatic steatosis. Collectively, we reveal an unexpected and novel function for Wnt10b in mediating the frequency of adipose-resident T cell subsets, that when knockdown skewing toward a Treg-dominated phenotype and further improving fat metabolism.

Impact of Solvents and Extraction Methods on the Insecticidal Activity of <i>Sesbania grandiflora</i> L. Leaf Extracts against Diamondback Moth, <i>Plutella xylostella</i>

Diamond back moth Plutella xylostella (L.) (Lepidoptera: Plutellidae), is a notorious pest of cruciferous crops causing extensive damage. The present study compares the insecticidal activity of Sesbania grandiflora extracts in hexane, ethyl acetate, and ethanol obtained from two extraction methods: Soxhlet and cold maceration against P. xylostella. Soxhlet extraction by all the solvents showed a distinct effect on larval mortality, adult emergence, and the growth and development of second-instar larvae than cold maceration extraction. Soxhlet ethanolic extract at 5% had significantly better insecticidal activity than cold maceration, with complete larval mortality. The antifeedant index was also higher in ethanol extract, followed by ethyl acetate and hexane extract. However, there was no significant variation in the developmental period. Thus, Soxhlet ethanolic extract of S. grandiflora is concluded to have a promising insecticidal activity on P. xylostella.

Distinct toxic effects, gene expression profiles, and phytohormone responses of Polygonatum cyrtonema exposed to two different antibiotics

The excessive usage of veterinary antibiotics has raised significant concerns regarding their environmental hazard and agricultural impact when entering surface water and soil. Animal waste serves as a primary source of organic fertilizer for intensive large-scale agricultural cultivation, including the widely utilized medicinal and edible plant, Polygonatum cyrtonem. In this study, we employed a novel plant stress tissue culture technology to investigate the toxic effects of tetracycline hydrochloride (TCH) and sulfadiazine (SDZ) on P. cyrtonema. TCH and SDZ exhibited varying degrees of influence on plant growth, photosynthesis, and the reactive oxygen species (ROS) scavenging system. Flavonoid levels increased following exposure to TCH and SDZ. The biosynthesis and signaling pathways of the growth hormones auxin and gibberellic acid were suppressed by both antibiotics, while the salicylic acid-mediated plant stress response was specifically induced in the case of SDZ. Overall, the study unveiled both common and unique responses at physiological, biochemical, and molecular levels in P. cyrtonema following exposure to two distinct types of antibiotics, providing a foundational framework for comprehensively elucidating the precise toxic effects of antibiotics and the versatile adaptive mechanisms in plants.

Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish.

Angiogenesis is a key process in embryonic development, a disruption of this process can lead to severe developmental defects, such as limb malformations. The identification of molecular perturbations representative of antiangiogenesis in zebrafish embryo (ZFE) may guide the assessment of developmental toxicity from an endpoint- to a mechanism-based approach, thereby improving the extrapolation of findings to humans. Thus, the aim of the study was to discover molecular changes characteristic of antiangiogenesis and developmental toxicity. We exposed ZFEs to two antiangiogenic drugs (SU4312, sorafenib) and two developmental toxicants (methotrexate, rotenone) with putative antiangiogenic action. Molecular changes were measured by performing untargeted metabolomics in single embryos. The metabolome response was accompanied by the occurrence of morphological alterations. Two distinct metabolic effect patterns were observed. The first pattern comprised common effects of two specific angiogenesis inhibitors and the known teratogen methotrexate, strongly suggesting a shared mode of action of antiangiogenesis and developmental toxicity. The second pattern involved joint effects of methotrexate and rotenone, likely related to disturbances in energy metabolism. The metabolites of the first pattern, such as phosphatidylserines, pterines, retinol, or coenzyme Q precursors, represented potential links to antiangiogenesis and related developmental toxicity. The metabolic effect pattern can contribute to biomarker identification for a mechanism-based toxicological testing.

Distinct effects of first-episode and recurrent major depressive disorder on brain changes related to suicidal ideation: Evidence from the REST-meta-MDD Project

BackgroundSignificant differences in clinical manifestations between first-episode and recurrent major depression disorder (FE-MDD/R-MDD) have been demonstrated in previous studies, including the degree of suicide attempt. However, the potential brain mechanism underlying the effect of depressive episode frequency on suicidal ideation (SI) remains unclear. MethodsIn this study, 102 patients with FE-MDD (SI/non-SI: N = 70/32) and 71 matched normal controls (NCs), as well as 75 patients with R-MDD (SI/non-SI: N = 37/38) and 49 matched NCs were screened from the Chinese REST-meta-MDD consortium. T1-weighted and resting-state fMRI images were used to calculate gray matter volume (GMV) and fractional amplitude of low-frequency fluctuations (fALFF), respectively. ResultsGroup comparisons revealed that FE-MDD showed changes only in GMV, while R-MDD showed changes in both GMV and fALFF compared to NCs. SI-specific GMV decreases were observed in the right cerebellum, superior marginal gyrus, and left middle temporal gyrus in FE-MDD patients, while SI-specific fALFF decreases in bilateral superior frontal gyrus and increases in bilateral cerebellum and left parahippocampal gyrus were obserevd in R-MDD patients. Moreover, a negative correlation was found between GMV value in right cerebellum and HAMD score. ConclusionsThese findings suggest that first-episode and recurrent MDD show different effects on brain structure and function in patients with SI, providing a potential explanation for the distinct clinical manifestations of MDD patients from a brain mechanisms perspective.

Development of a Relationship between Pavement Condition Index and Riding Quality Index on Rural Roads: A Case Study in China

The current standard for evaluating road conditions worldwide relies primarily on the Pavement Condition Index (PCI) and the International Roughness Index (IRI). The IRI can be further calculated to obtain the Riding Quality Index (RQI). To assess pavement damage, various imaging equipment is commonly utilized, providing consistent results that align with actual road conditions. For roughness detection, the Laser Profilometer offers excellent results but may not be suitable for rural roads with poor conditions due to its high inspection cost and the need for a stable environmental setting. Therefore, there is a pressing need to develop cost-effective, rapid, and accurate roughness inspection methods for these roads, which constitute a significant portion of the road network. This study examined the relationship between PCI and RQI using nonlinear regression on 30,088 valid pavement inspection records from various regions in China (totaling 24,624.222 km). Our objective was to estimate RQI solely from PCI data, capitalizing on its broad coverage and superior accuracy. Additionally, we explored how PCI levels impact RQI decay rates. The models in this study were compared to several models published in previous studies at last. Our findings indicate that the model performs best for low-grade roads with low PCI scores, achieving over 90% accuracy for both cement concrete and asphalt concrete pavements. Furthermore, different levels of pavement damage have distinct effects on RQI decay rates, with the most significant impact observed when the pavement is severely damaged. The models in this study outperformed all the other available models in the literature. Consequently, under limited inspection conditions in rural areas, pavement damage inspection results can effectively predict riding quality or roughness, thereby reducing inspection costs. Overall, this study offers valuable insights but has limitations, including limited global generalizability and the model’s applicability to high-grade roads. Future research is needed to address these issues and enhance practical applications.