Spartina alterniflora invasion decouples multiple elements in coastal wetland soils.

Deciphering the biogeochemical coupling of multiple elements in soils could better mechanistic understanding of ecosystem stability response to the alien invasion. The coupling of 45 elements in soils from wetlands covered by Spartina alterniflora (Sa) was compared with that in soils covered by native Phragmites australis (Pa) in coastal regions of China. Results showed that S. alterniflora invasion not only significantly reshaped geochemical enrichment and dispersion states, but also decoupled the coupling of multiple elements in soils compared with Pa. Atomic mass emerged as the primary factor governing the coupling of multiple elements, of which a significantly positive correlation exhibited between atomic mass with elemental coupling in Pa, but no such relation was observed in SaThe coupling of lighter elements was more susceptible to and generally enhanced by the invasion of S. alterniflora compared to the heavier, of which carbon, iron (Fe), and cadmium (Cd) had the highest susceptibility. Besides atomic mass, biological processes (represented by soil organic carbon, nitrogen, phosphorus, and sulfur), interactions between sea and land (represented by salinity and pH), and their combination explained 17 %, 10 %, and 13 % variation in the coupling of multiple elements, respectively. The present work confirmed that S. alterniflora invasion was the important factor driving soil multi-element cycling and covariation in coastal wetlands.

Hippocampal Subregions Volume and Texture for the Diagnosis of Mild Cognitive Impairment.

The aim was to examine the diagnostic efficacy of hippocampal subregions volume and texture in differentiating amnestic mild cognitive impairment (MCI) from normal aging changes. Ninety MCI subjects and eighty-eight well-matched healthy controls (HCs) were selected. Twelve hippocampal subregions volume and texture features were extracted using Freesurfer and MaZda based on T1 weighted MRI. Then, two-sample t-test and Least Absolute Shrinkage and Selection Operator (LASSO) regression were developed to select a subset of the original features. Support vector machine (SVM) was used to perform the classification task and the area under the curve (AUC), sensitivity, specificity and accuracy were calculated to evaluate the diagnostic efficacy of the model. The volume features with high discriminative power were mainly located in the bilateral CA1 and CA4, while texture feature were gray-level non-uniformity, run length non-uniformity and fraction. Our model based on hippocampal subregions volume and texture features achieved better classification performance with an AUC of 0.90. The volume and texture of hippocampal subregions can be utilized for the diagnosis of MCI. Moreover, we found that the features that contributed most to the model were mainly textural features, followed by volume. These results may guide future studies using structural scans to classify patients with MCI.

PcENO3 interacts with patchoulol synthase to positively affect the enzymatic activity and patchoulol biosynthesis in Pogostemon cablin.

Patchouli alcohol, a significant bioactive component of the herbal plant Pogostemon cablin, has considerable medicinal and commercial potential. Several genes and transcription factors involved in the biosynthesis pathway of patchouli alcohol have been identified. However, so far, regulatory factors directly interacting with patchouli synthase (PTS) have not been reported. This study was conducted to analyze the interaction between PcENO3 and PcPTS to explore the molecular regulation effect of PcENO3 on patchouli alcohol biosynthesis. PcENO3, a homologous protein of Arabidopsis ENO3 belonging to the enolase family, was identified and characterized. Subcellular localization experiments in Arabidopsis protoplast cells indicated that the PcENO3 protein was localized in both the cytoplasm and nucleus. The physical interaction between PcENO3 and PcPTS was confirmed through yeast two-hybrid (Y2H), GST pull-down, and bimolecular fluorescence complementation assays. Furthermore, the Y2H assay demonstrated that PcENO3 could also interact with JAZ proteins in the JA pathway. Enzymatic assays showed that the interaction with PcENO3 increased the catalytic activity of patchoulol synthase. Additionally, suppression of PcENO3 expression with VIGS (virus-induced gene silencing) decreased patchouli alcohol content compared to the control. These findings suggest that PcENO3 interacts with patchoulol synthase and modulates patchoulol biosynthesis by enhancing the enzymatic activity of PcPTS.

Mettl1-mediated internal m7G methylation of Sptbn2 mRNA elicits neurogenesis and anti-alzheimer's disease.

BACKGROUND: N7-methylguanosine (m7G) is one of the most conserved modifications in nucleosides impacting mRNA export, splicing, and translation. However, the precise function and molecular mechanism of internal mRNA m7G methylation in adult hippocampal neurogenesis and neurogenesis-related Alzheimer's disease (AD) remain unknown. RESULTS: We profiled the dynamic Mettl1/Wdr4 expressions and m7G modification during neuronal differentiation of neural stem cells (NSCs) in vitro and in vivo. Adult hippocampal neurogenesis and its molecular mechanisms were examined by morphology, biochemical methods and biological sequencing. The translation efficiency of mRNA was detected by polysome profiling. The stability of Sptbn2 mRNA was constructed by RNA stability assay. APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as model of AD. Morris water maze was used to detect the cognitive function. METHODS: We found that m7G methyltransferase complex Mettl1/Wdr4 as well as m7G was significantly elevated in neurons. Functionally, silencing Mettl1 in neural stem cells (NSCs) markedly decreased m7G modification, neuronal genesis and proliferation in addition to increasing gliogenesis, while forced expression of Mettl1 facilitated neuronal differentiation and proliferation. Mechanistically, the m7G modification of Sptbn2 mRNA by Mettl1 enhanced its stability and translation, which promoted neurogenesis. Importantly, genetic defciency of Mettl1 reduced hippocampal neurogenesis and spatial memory in the adult mice. Furthermore, Mettl1 overexpression in the hippocampus of APP/PS1 mice rescued neurogenesis and behavioral defects. CONCLUSION: Our findings unravel the pivotal role of internal mRNA m7G modification in Sptbn2-mediated neurogenesis, and highlight Mettl3 regulation of neurogenesis as a novel therapeutic target in AD treatment.

Low-density polyethylene microplastics and biochar interactively affect greenhouse gas emissions and microbial community structure and function in paddy soil.

Paddy soils are susceptible to microplastics (MPs) contamination. As a common soil amendment, biochar (BC) has been extensively applied in paddy fields. The co-occurrence of MPs and BC may cause interactive effects on soil biogeochemical processes, which has yet been well studied. In this study, a 41-days of microcosm experiment was conducted using paddy soil added with 0.5-1.5 wt% of low-density polyethylene (LDPE) and 5 wt% of BC individually or jointly. Application of BC, LDPE, or their mixture into soil significantly increased the emission of methane (CH4), but suppressed the emission of carbon dioxide (CO2). LDPE addition lowered soil nitrous oxide (N2O) emissions, while BC exerted an opposite effect. Proteobacteria was the most dominant phylum with a relative abundance range of 35.1-51.0%, followed by Actinobacteria (19.3-30.9%) and Acidobacteria (7.5-23.5%). The abundances of the mcrA gene and pH values were increased in soils added with BC or/and LDPE, which were the possible reasons for the higher CH4 emissions in these treatments. The emission of N2O was positively related to the abundances of norB and narG genes, suggesting denitrification was a major pathway to produce N2O. Results of structural equation modeling demonstrated that addition of BC or/and LDPE MPs could affect greenhouse gas emissions from paddy soil by altering soil chemical properties, microbial community structure, and functional gene abundances.

Combination of mineral protection and molecular characteristics rather than alone to govern soil organic carbon stability in Qinghai-Tibetan plateau wetlands.

Wetlands in the Yarlung Tsangpo River Basin (YTR) on the Qinghai-Tibet Plateau provide immense soil organic carbon (SOC) storage, which is highly susceptible to climate warming and requires urgent deciphering SOC stabilization mechanisms of long-term protection of SOC against decomposition. Conflicting views exist regarding whether persistent SOC is controlled by molecular features or by mineral protection. As such, this study quantified SOC stability using two thermal indices (TG-T50, and DSC), described molecular features of SOC using pyrolysis-gas chromatography-mass spectrometry, and measured SOC protection by minerals using a chemical extraction method. Results indicated SOC of topsoils had higher thermal stability, with TG-T50 and DSC-T50 of 337.61 °C and 384.58 °C, than that of subsoils with TG-T50 and DSC-T50 of 337.32 and 382.67 °C, respectively. We found subsoils had significantly higher proportions of aliphatic and aromatic compounds, while existed higher SOC associated with minerals. It seemed SOC stabilization differed with soil depths, in which mineral protection dictated SOC thermal stability in topsoils while molecular features posed a more important constraint on SOC stabilization in subsoils. Overall, our findings support the hypothesis of physical and chemical protection but emphasized that SOC thermal stability largely depended on to extent of the combination between molecular features and mineral protection, which explained 55% in topsoils and 73% in subsoils, respectively.

Patterns and drivers of soil surface-dwelling Oribatida diversity along an altitudinal gradient on the Changbai Mountain, China.

Distribution patterns of biodiversity and environmental interactions are dominant themes in ecology. In montane ecosystems, biodiversity is closely associated with altitudinal gradients. However, studies of biodiversity in montane ecosystems are focused on plants and vertebrates, with relatively less on invertebrates. Here, the present study used a Vortis arthropod suction sampler to explore the biodiversity patterns of soil surface-dwelling Oribatida and their drivers along an altitudinal gradient (600, 800, 1600, 2000, and 2300 m) from typical temperate forests, evergreen coniferous forests, subalpine birch forests to alpine tundra on the north slope of Changbai Mountain, Northeast China. Trichoribates berlesei, Platynothrus peltifer, and Oribatula tibialis were the dominant soil surface-dwelling species on Changbai Mountain. Generally, alpha diversity and beta diversity of soil surface-dwelling Oribatida decreased with the rising altitude, with a peaking density value at 2000 m. The result of beta diversity showed that the structures of community were more influenced by the species turnover component than the nestedness component. Nonmetric multidimensional scaling (NMDS) ordination showed that the community structure of soil surface-dwelling Oribatida varied significantly along the altitudinal gradient. The variance partitioning showed that the elevation and climatic conditions determined the soil surface-dwelling Oribatida community. Spatial filtering represented by geographic and elevation distances was particularly associated with soil surface-dwelling Oribatida community variation between altitudes on Changbai Mountain. However, the variation of the Oribatida community between adjacent altitudes was only associated with geographic distance. Our study provides supportive evidence for the biodiversity analyzing of soil surface-dwelling Oribatida in montane ecosystems along an altitudinal gradient.

Feasibility of 3.0 T balanced fast field echo non-contrast-enhanced whole-heart coronary magnetic resonance angiography.

Background: Coronary artery disease (CAD) is one of the most common diseases seriously harmful to human health caused by atherosclerosis. Besides coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA), coronary magnetic resonance angiography (CMRA) has become an alternative examination. The purpose of this study was to prospectively evaluate the feasibility of 3.0 T free-breathing whole-heart non-contrast-enhanced coronary magnetic resonance angiography (NCE-CMRA). Methods: After Institutional Review Board approval, the NCE-CMRA data sets of 29 patients acquired successfully at 3.0 T were evaluated independently by two blinded readers for visualization and image quality of coronary arteries using the subjective quality grade. The acquisition times were recorded in the meantime. A part of the patients had undergone CCTA, we represented stenosis by scores and used the Kappa to evaluate the consistency between CCTA and NCE-CMRA. Results: Six patients did not get diagnostic image quality because of severe artifacts. The image quality score assessed by both radiologists is 3.2±0.7, which means the NCE-CMRA can show the coronary arteries excellently. The main vessels of the coronary artery on NCE-CMRA images are considered reliably assessable. The acquisition time of NCE-CMRA, is 8.8±1.2 min. The Kappa of CCTA and NCE-CMRA on detecting stenosis is 0.842 (P<0.001). Conclusions: The NCE-CMRA results in reliable image quality and visualization parameters of coronary arteries within a short scan time. The NCE-CMRA and CCTA have a good agreement for detecting stenosis.

Radiomics nomogram for predicting axillary lymph node metastasis in breast cancer based on DCE-MRI: A multicenter study.

OBJECTIVES: This study aims to develop and validate a radiomics nomogram based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to noninvasively predict axillary lymph node (ALN) metastasis in breast cancer. METHODS: This retrospective study included 263 patients with histologically proven invasive breast cancer and who underwent DCE-MRI examination before surgery in two hospitals. All patients had a defined ALN status based on pathological examination results. Regions of interest (ROIs) of the primary tumor and ipsilateral ALN were manually drawn. A total of 1,409 radiomics features were initially computed from each ROI. Next, the low variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) algorithms were used to extract the radiomics features. The selected radiomics features were used to establish the radiomics signature of the primary tumor and ALN. A radiomics nomogram model, including the radiomics signature and the independent clinical risk factors, was then constructed. The predictive performance was evaluated by the receiver operating characteristic (ROC) curves, calibration curve, and decision curve analysis (DCA) by using the training and testing sets. RESULTS: ALNM rates of the training, internal testing, and external testing sets were 43.6%, 44.3% and 32.3%, respectively. The nomogram, including clinical risk factors (tumor diameter) and radiomics signature of the primary tumor and ALN, showed good calibration and discrimination with areas under the ROC curves of 0.884, 0.822, and 0.813 in the training, internal and external testing sets, respectively. DCA also showed that radiomics nomogram displayed better clinical predictive usefulness than the clinical or radiomics signature alone. CONCLUSIONS: The radiomics nomogram combined with clinical risk factors and DCE-MRI-based radiomics signature may be used to predict ALN metastasis in a noninvasive manner.

Decreased Regional Spontaneous Brain Activity and Cognitive Dysfunction in Patients with Coronary Heart Disease: a Resting-state Functional MRI Study.

OBJECTIVES: Chronic coronary heart disease (CHD) is correlated with an increased risk of cognitive impairment (CI), but the mechanisms underlying these changes remain unclear. The aim of the present study was to explore the potential changes in regional spontaneous brain activities and their association with CI, to explore the pathophysiological mechanisms underlying CI in patients with CHD. MATERIALS AND METHODS: A total of 71 CHD patients and 73 matched healthy controls (HCs) were included in this study. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess the participants' cognitive functions. Regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuation(fALFF) values were calculated to determine regional spontaneous brain activity. Coronary artery calcium (CAC) score provides a measure of the total coronary plaque burden. Mediation analyses were performed to test whether CHD's effects on cognitive decline are mediated by decreased regional spontaneous brain activity. RESULTS: Patients with CHD had significantly lower MMSE and MoCA scores than the HCs. Compared with the HCs, the patients with CHD demonstrated significantly decreased ReHo and fALFF values in the bilateral medial superior frontal gyrus (SFGmed), left superior temporal gyrus (TPOsup) and left middle temporal gyrus (TPOmid). Impaired cognitive performance was positively correlated with decreased activities in the SFGmed. Mediation analyses revealed that the decreased regional spontaneous brain activity in the SFGmed played a critical role in the relationship between the increase in CAC score and the MoCA and MMSE scores. CONCLUSION: The abnormalities of spontaneous brain activity in SFGmed may provide insights into the neurological pathophysiology underlying CHD associated with cognitive dysfunction.

Impacts of spectral characteristics of dissolved organic matter on methylmercury contents in peatlands, Northeast China.

Dissolved organic matter (DOM) plays an important role in promoting or suppressing methylmercury (MeHg) production in wetlands. However, the effects of DOM spectral characteristics on MeHg levels remain poorly understood in boreal peatlands in Northeast China, where is undergoing remarkable climate warming. In the present work, soil samples were collected from 22 peatlands in the Greater Khingan Mountains (GKM) to test the hypothesis that DOM spectral properties control MeHg levels. DOM was characterized by UV-Vis absorption and fluorescence spectroscopy; the three-dimensional fluorescence excitation-emission matrix (EEM) was used to unveil the origin of DOM. The average total mercury (THg) and MeHg contents were 112.76 µg/kg and 12.43 µg/kg across all peatlands, respectively. There was a significantly positive correlation between MeHg and the longitude spanning the range from 120 to 123°E (p < 0.05). Proportions of MeHg to THg (%MeHg), 12.3% on average, were positively correlated with DOM humification degree at p < 0.05 level. Protein-like components of DOM (P-like) were negatively related to %MeHg. DOM had positive effects on THg, and P-like components, HIX and BIX can negatively affect THg as well as MeHg. Our findings demonstrate that the spectral characteristics of DOM in soil are crucial to the content of methyl mercury in the GKM soil.

Ant colonization increased total mercury but reduced methylmercury contents in boreal mires, Northeast China.

Soil macroinvertebrates as ecosystem engineers play significant, but largely ignored, roles in affecting mercury (Hg) cycle by altering soil physical-chemical properties. Ant is likely expanded into boreal mires with climate warming, however, its impacts on Hg cycle remained poorly understood. We compared total Hg (THg) and methylmercury (MeHg) contents in soils from antmounds (Lasius flavus) and the nearby ambient in a boreal mire in Northeast China. The present work seeks to unravel factors that controlling MeHg levels in case of ant appearance or absence. The average THg was 179 µg/kg in the ant mound and was 106.1 µg/kg in nearby soils, respectively. The average MeHg was 10.9 µg/kg in the ant mound and was 12.9 µg/kg in nearby soils, respectively. The ratios of MeHg to THg (%MeHg) were 7.61% in ant mounds and 16.75% in nearby soils, respectively. Ant colonization caused THg enrichment and MeHg depletion, and this change was obvious in the 10-20 cm depth soil layer where ants mainly inhabited. Spectrometry characteristics of soil dissolved organic matter (DOM) exert a stronger control than microorganisms on MeHg variation in soils. A structural equation model revealed that the molecular weight of DOM inhibited MeHg irrespective of ant presence or absence, while humification conducive to MeHg significantly in ant mound soils. Microorganisms mainly affected Hg methylation by altering the molecular weight and humification of DOM. We propose that the effects of ant colonization on MeHg rested on DOM feature variations caused by microorganisms in boreal mires.

Altered dynamic amplitude of low-frequency fluctuations in patients with postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a common mood disorder with increasing incidence year by year. However, the dynamic changes in local neural activity of patients with PPD remain unclear. In this study, we utilized the dynamic amplitude of low-frequency fluctuation (dALFF) method to investigate the abnormal temporal variability of local neural activity and its potential correlation with clinical severity in PPD. METHODS: Twenty-four patients with PPD and nineteen healthy primiparous mothers controls (HCs) matched for age, education level and body mass index were examined by resting-state functional magnetic resonance imaging (rs-fMRI). A sliding-window method was used to assess the dALFF, and a k-means clustering method was used to identify dALFF states. Two-sample t-test was used to compare the differences of dALFF variability and state metrics between PPD and HCs. Pearson correlation analysis was used to analyze the relationship between dALFF variability, states metrics and clinical severity. RESULTS: (1) Patients with PPD had lower variance of dALFF than HCs in the cognitive control network, cerebellar network and sensorimotor network. (2) Four dALFF states were identified, and patients with PPD spent more time on state 2 than the other three states. The number of transitions between the four dALFF states increased in the patients compared with that in HCs. (3) Multiple dALFF states were found to be correlated with the severity of depression. The variance of dALFF in the right middle frontal gyrus was negatively correlated with the Edinburgh postnatal depression scale score. CONCLUSION: This study provides new insights into the brain dysfunction of PPD from the perspective of dynamic local brain activity, highlighting the important role of dALFF variability in understanding the neurophysiological mechanisms of PPD.

Exploring spatial heterogeneity and factors influencing construction and demolition waste in China.

Natural disasters, new urbanization, and urban renewal activities generated a large amount of construction and demolition waste (C&DW), and managing C&DW has become an urgent problem to be solved in the construction of "Zero-waste cities." Based on the calculation of C&DW generation in China from 2005 to 2019, this study explored spatial heterogeneity and factors influencing C&DW in China by Exploratory Spatial Data Analysis (ESDA) and Geographically Weighted Regression (GWR) method. The results showed that C&DW generation in China increased every year, and the overall distribution was characterized as "high in the east and low in the west," with distinct regional differences. The generation intensity of C&DW in China showed a decreasing trend every year. The regions with rapid growth of C&DW generation were concentrated in the eastern coastal areas, and there was significant spatial heterogeneity in the growth trend. There is a significant spatial autocorrelation in C&DW generation in China. The factors of population size, per capita gross domestic product, and the scale of the construction industry played a positive role in promoting C&DW generation in each province, whereas labor efficiency played a negative role inhibiting C&DW generation, which has a significant temporal and spatial heterogeneity. The results extend C&DW management theory and help the policy maker to formulate regional differentiation policies as China and developing country.

Deep Learning-Based Diffusion-Weighted Magnetic Resonance Imaging in the Diagnosis of Ischemic Penumbra in Early Cerebral Infarction.

The prefiltered image was imported into the local higher-order singular value decomposition (HOSVD) denoising algorithm (GL-HOSVD)-optimized diffusion-weighted imaging (DWI) image, which was compared with the deviation correction nonlocal mean (NL mean) and low-level edge algorithm (LR + edge). Regarding the peak signal-to-noise ratio (PSNR), root mean square error (RMSE), sensitivity, specificity, accuracy, and consistency, the application effect of the GL-HOSVD algorithm in DWI was investigated, and its adoption effect in the examination of ischemic penumbra (IP) of early acute cerebral infarction (ACI) patients was evaluated. A total of 210 patients with ACI were selected as the research subjects, who were randomly rolled into two groups. Those who were checked by conventional DWI were set as the control group, and those who used DWI based on the GL-HOSVD denoising algorithm were set as the observation group, with 105 people in each. Positron emission tomography (PET) test results were set as the gold standard to evaluate the application value of the two examination methods. It was found that under different noise levels, the peak signal-to-noise ratio (PSNR) of the GL-HOSVD algorithm and the root mean square error (RMSE) of the FA parameter were better than those of the nonlocal means (NL-means) of deviation correction and low-rank edge algorithm (LR + edge). The sensitivity, specificity, accuracy, and consistency (8.76%, 81.25%, 87.62%, and 0.52) of the observation group were higher than those of the control group (57.78%, 53.33%, 57.14%, and 0.35) (P < 0.05). Moreover, the apparent diffusion coefficient (ADC) of the DWI images of the observation group was basically consistent with that of the PET images, while the control group had a poor display effect and low definition. In summary, under different noise levels, the GL-HOSVD algorithm had a good denoising effect and greatly reduced fringe artifacts. DWI after denoising had high sensitivity, specificity, accuracy, and consistency in the detection of IP, which was worthy of clinical application and promotion.

Gluteus maximus metastasis from sacrococcygeal chordoma: A case report.

We reported the metastatic chordoma in the right gluteus maximus of a 73-year-old man. The patient was initially diagnosed with sacrococcygeal chordoma and treated with surgical resection. Unfortunately, he had a gluteal metastasis and recurrence and suffered the third-operation therapy. Chordoma is a rare malignant tumor and may metastasize, but the metastasis and recurrence of chordoma at the right gluteus maximus following sacrococcygeal region are extraordinarily rare. This unusual case report may be helpful to clinical workers in diagnosing chordoma.

A study on the spatial network characteristics and effects of CDW generation in China.

In this paper, the province construction and demolition waste (CDW) generation in China from 2005 to 2018 is calculated by using the area estimation method. Together with the use of the gravity model and the social network analysis method (SNA), the characteristics and effects of the spatial correlation structure network of China's province construction and demolition waste generation are studied. It has been found that from 2005 to 2018, the construction and demolition waste in China had seen a significant rise, and the spatial difference in province generation is significant. During that time, China's inter-provincial construction and demolition waste generation demonstrated significant characteristics of a spatial correlation network with a complex network hierarchy and showed a trend of year-by-year increase in its overall network density and number of correlation. In this spatial connection network, nine provinces, including Beijing, Tianjin, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong, Hubei and Guangdong, played a core role as "bridges", Beijing, Shanghai, Jiangsu, Guangdong, Shandong, Fujian and Zhejiang provinces are "beneficiaries", Chongqing, Tianjin, Hubei, Anhui, Sichuan, Henan, Jiangxi, Hunan and Hebei are "brokers" while other provinces are "the damaged". Indexes such as network density, network hierarchy and network efficiency all have a significant impact on the national construction and demolition waste generation intensity. The reduction of network density, the improvement of network hierarchy and network efficiency can significantly reduce the difference in construction and demolition waste generation intensity. The structure of spatial correlation network has significant influence on the difference of construction and demolition waste generation intensity.

Altered structural covariance of hippocampal subregions in patients with Alzheimer's disease.

BACKGROUND AND PURPOSE: Different atrophy of hippocampus subregions is a valuable indicator of patients with Alzheimer's disease (AD). To explore the relationship among the hippocampal subregions of patients with AD, altered gray matter structural covariance of hippocampal subregions in patients with AD was studied. MATERIALS AND METHODS: Participants were selected from the Open Access Series of Imaging Studies Database. Pearson correlations among the volume of the hippocampal subregions were generated as structural covariance network. Topological metrics for all selected sparsity ranges were calculated in the healthy controls (HCs) and patients with AD by using the GRETNA software package. Spearman correlation analysis was performed to statistically analyze the volume and Mini-mental State Examination (MMSE) scores of the hippocampal subregions of the patients with AD, with age and gender as interference covariates and corrected for false discovery rate (FDR) (p < 0.05). RESULTS: The structural covariance network properties of the hippocampal subregions of patients with AD changed. The clustering coefficient (Cp) and network efficiency (Ne) decreased, characteristic path length (Lp) increased, and the hub nodes changed. The volumes of left parasubiculum, right granule cell layer of dentate gyrus (GC-DG), right molecular layer of the hippocampus (molecular_layer_HP), right Cornu Ammonis (CA) regions CA1 of the hippocampus proper, right fimbria and right CA4 were significantly correlated with the MMSE scores. CONCLUSIONS: The structural covariance network of the hippocampal subregions of patients with AD was reorganized, and the transmission efficiency was weakened. This study explored the changes in these subregions from the network level, which may provide a new perspective and theoretical basis for the neurobiological mechanisms of patients with AD.

Spontaneous Selection of Cryptosporidium Drug Resistance in a Calf Model of Infection.

The intestinal protozoan Cryptosporidium is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ∼10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA (Cryptosporidium parvum MetRS [CpMetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance. Dairy calves experimentally infected with Cryptosporidium parvum initially improved with 2093 treatment, but parasite shedding resumed in two of three calves on treatment day 5. Parasites shed by each recrudescent calf had different amino acid-altering mutations in the gene encoding CpMetRS (CpMetRS), yielding either an aspartate 243-to-glutamate (D243E) or a threonine 246-to-isoleucine (T246I) mutation. Transgenic parasites engineered to have either the D243E or T246I CpMetRS mutation using CRISPR/Cas9 grew normally but were highly 2093 resistant; the D243E and T246I mutant-expressing parasites, respectively, had 2093 half-maximal effective concentrations (EC50s) that were 613- and 128-fold that of transgenic parasites with wild-type CpMetRS. In studies using recombinant enzymes, the D243E and T246I mutations shifted the 2093 IC50 >170-fold. Structural modeling of CpMetRS based on an inhibitor-bound Trypanosoma brucei MetRS crystal structure suggested that the resistance mutations reposition nearby hydrophobic residues, interfering with compound binding while minimally impacting substrate binding. This is the first report of naturally emerging Cryptosporidium drug resistance, highlighting the need to address the potential for anticryptosporidial resistance and establish strategies to limit its occurrence.

Methionyl-tRNA synthetase inhibitor has potent in vivo activity in a novel Giardia lamblia luciferase murine infection model.

BACKGROUND: Methionyl-tRNA synthetase (MetRS) inhibitors are under investigation for the treatment of intestinal infections caused by Giardia lamblia. OBJECTIVES: To properly analyse the therapeutic potential of the MetRS inhibitor 1717, experimental tools including a robust cell-based assay and a murine model of infection were developed based on novel strains of G. lamblia that employ luciferase reporter systems to quantify viable parasites. METHODS: Systematic screening of Giardia-specific promoters and luciferase variants led to the development of a strain expressing the click beetle green luciferase. Further modifying this strain to express NanoLuc created a dual reporter strain capable of quantifying parasites in both the trophozoite and cyst stages. These strains were used to develop a high-throughput cell assay and a mouse infection model. A library of MetRS inhibitors was screened in the cell assay and Compound-1717 was tested for efficacy in the mouse infection model. RESULTS: Cell viability in in vitro compound screens was quantified via bioluminescence readouts while infection loads in mice were monitored with non-invasive whole-animal imaging and faecal analysis. Compound-1717 was effective in clearing mice of Giardia infection in 3 days at varying doses, which was supported by data from enzymatic and phenotypic cell assays. CONCLUSIONS: The new in vitro and in vivo assays based on luciferase expression by engineered G. lamblia strains are useful for the discovery and development of new therapeutics for giardiasis. MetRS inhibitors, as validated by Compound-1717, have promising anti-giardiasis properties that merit further study as alternative therapeutics.