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Background and purposeInfantile cerebellar retinal degeneration (ICRD) (OMIM #614559) is a rare autosomal recessive inherited disease associated with mutations in the aconitase 2 (ACO2) gene. We report a Chinese girl with novel compound heterozygous variants in ACO2, who presented at 7 months of age with psychomotor retardation, truncal hypotonia, and ophthalmologic abnormalities. This study aims to investigate the potential molecular mechanisms underlying ACO2 deficiency-induced neuropathy.MethodsWhole exome sequencing was performed on family members to screen for potential pathogenic mutations, followed by Sanger sequencing for validation. Mitochondrial aconitase activity and mitochondrial DNA (mtDNA) copy number were measured using an aconitase activity detection kit and quantitative PCR, respectively. Transcriptome expression profiles from patient cells, and cerebellar and retinal organoids retrieved from the GEO database were integrated. Functional enrichment analysis and protein-protein interaction networks were used to identify key molecules, and their expression levels were validated using Western blot analysis.ResultsGenetic testing revealed novel compound heterozygous variations in the proband's ACO2 gene (NM:001098), including c.854A>G (p.Asn285Ser) and c.1183C>T (p.Arg395Cys). Predictive analysis of the tertiary structure of the ACO2 protein suggests that both p.Asn285Ser and p.Arg395Cys affect the binding ability of ACO2 to ligands. The mitochondrial aconitase activity and mtDNA copy number in the proband's leukocytes were significantly reduced. Transcriptomic data analysis identified 80 key candidate genes involved in ACO2-related neuropathy. Among these, LRP8 and ANK3, whose gene expression levels were significantly positively correlated with ACO2, were further validated by Western blot analysis.ConclusionsThis study expands the spectrum of pathogenic ACO2 variants, elucidates the potential molecular mechanisms underlying ACO2-related neuropathy, provides in-depth support for the pathogenicity of ACO2 genetic variations, and offers new insights into the pathogenesis of ICRD.

AimWhite matter hyperintensities (WMH) and lacunes were important features of cerebral small vessel disease (CSVD), which contributes to 25% of ischemic strokes and 45% of dementias. Currently, the underlying mechanisms of WMH and lacunes are not clear, and the role of hemodynamic changes is not fully investigated. In this study, we aimed to measure the cerebral blood flow (CBF) and arterial transit in CSVD patients and to investigate their association with WMH and lacunes.MethodsWe retrospectively analyzed the prospectively collected database of CSVD patients. Ninety-two CSVD patients with complete imaging data were included. We used arterial spin labeling (ASL) with post-labeling delay time (PLD) of 1,525 ms and 2,025 ms to measure CBF respectively, and the difference between CBFPLD1.5 and CBFPLD2.0 was recorded as δCBF. We performed regression analysis to understand the contribution of CBF, δCBF to CSVD imaging markers.ResultsWe found that CBF derived from both PLDs was associated with WMH volume and the presence of lacune. CBFPLD1.5 was significantly lower than CBFPLD2.0 in CSVD patients, and δCBF was correlated with WMH volume but not the presence of lacune. Furthermore, CBFPLD2.0 and δCBF were both associated with WMH in multiple regression analyses, suggesting an independent effect of delayed arterial transit. On an exploratory basis, we also investigated the relationship between venous disruption on δCBF, and we found that δCBF correlated with deep medullary veins score.ConclusionBoth CBF and arterial transit were associated with WMH. ASL with multiple PLDs could provide additional hemodynamic information to CSVD-related studies.

Natural edible oil derived from wild non-cultivated oil crops contributed to human daily nutritional diversity and disease prevention. It was important to investigate the nutritional value of these oils and the feasibility of crop cultivation. The present study focused on the assessment of seed oil quality of Sambucus williamsii Hance (SWH) and its molecular breeding. Wild SWH seed oil was extracted by supercritical CO2 technology and the composition of the oil was determined by using gas chromatography mass spectrometry (GC-MS) analysis. The oil content of SWH seeds reaches around 40%. Its seed oil was found to be rich in unsaturated fatty acids, such as 24.24% of linolenic acid and 50.56% of linoleic acid, and vitamin E (25.92 mg kg−1). The cytotoxicity and heavy metal analysis showed SWH seed oil was safe for consumption. In addition, the SWH strains with excellent characteristics were screened out for cultivation according to genetic diversity and morphological analysis. Amplified fragment length polymorphism (AFLP) markers were used to evaluate the genetic diversity of 28 accessions of wild SWH seeds and 5 accessions were selected to cultivate. Among them, two strains of SWH (sample 3 and 6) with high yielding (275.7 and 266.8 area yield kg−1) were suitable for dense planting and could be used to establish the raw material forest of SWH seed oil. The results of this study indicated the potential of development of selected SWH as novel oil crops and their wide cultivation.

Streptococcus mutans (S. mutans), the prime pathogen of dental caries, can secrete glucosyltransferases (GTFs) to synthesize extracellular polysaccharides (EPSs), which are the virulence determinants of cariogenic biofilms. Ursolic acid, a type of pentacyclic triterpene natural compound, has shown potential antibiofilm effects on S. mutans. To investigate the mechanisms of ursolic acid-mediated inhibition of S. mutans biofilm formation, we first demonstrated that ursolic acid could decrease the viability and structural integrity of biofilms, as evidenced by XTT, crystal violet, and live/dead staining assays. Then, we further revealed that ursolic acid could compete with the inherent substrate to occupy the catalytic center of GTFs to inhibit EPS formation, and this was confirmed by GTF activity assays, computer simulations, site-directed mutagenesis, and capillary electrophoresis (CE). In conclusion, ursolic acid can decrease bacterial viability and prevent S. mutans biofilm formation by binding and inhibiting the activity of GTFs.

The immunotherapeutic treatment of various cancers with an increasing number of immune checkpoint inhibitors (ICIs) has profoundly improved the clinical management of advanced diseases. However, just a fraction of patients clinically responds to and benefits from the mentioned therapies; a large proportion of patients do not respond or quickly become resistant, and hyper- and pseudoprogression occur in certain patient populations. Furthermore, no effective predictive factors have been clearly screened or defined. In this review, we discuss factors underlying the elucidation of potential immunotherapeutic resistance mechanisms and the identification of predictive factors for immunotherapeutic responses. Considering the heterogeneity of tumours and the complex immune microenvironment (composition of various immune cell subtypes, disease processes, and lines of treatment), checkpoint expression levels may not be the only factors underlying immunotherapy difficulty and resistance. Researchers should consider the tumour microenvironment (TME) landscape in greater depth from the aspect of not only immune cells but also the tumour histology, molecular subtype, clonal heterogeneity and evolution as well as micro-changes in the fine structural features of the tumour area, such as myeloid cell polarization, fibroblast clusters and tertiary lymphoid structure formation. A comprehensive analysis of the immune and molecular profiles of tumour lesions is needed to determine the potential predictive value of the immune landscape on immunotherapeutic responses, and precision medicine has become more important.

Assessing glymphatic function using in-vivo imaging method is of great value for understanding its contribution to major brain diseases. In the present study, we aim to validate the association between a variety of risk factors and a potential index of glymphatic function—Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS index). We enrolled 142 subjects from communities and performed multi-modality magnetic resonance imaging scans. The ALPS index was calculated from diffusion tensor imaging data, and its associations with demographic factors, vascular factors were investigated using regression analyses. We found that the ALPS index was negatively associated with age (β = −0.284, p < 0.001). Compared to males, females had significantly higher ALPS index (β = −0.243, p = 0.001). Hypertensive subjects had significantly lower ALPS index compared to non-hypertensive subjects (β = −0.189, p = 0.013). Furthermore, venous disruption could decrease ALPS index (β = −0.215, p = 0.003). In general, our results are in consistent with previous conceptions and results from animal studies about the pathophysiology of glymphatic dysfunction. Future studies utilizing this method should consider introducing the above-mentioned factors as important covariates.

Lenticulostriate arteries (LSAs) supply blood to important subcortical areas and are, therefore, essential for maintaining the optimal functioning of the brain’s most metabolically active nuclei. Past studies have demonstrated the potential for quantifying the morphology of LSAs as biomarkers of vascular fragility or underlying arteriopathies. Thus, the current study aims to evaluate the morphological features of LSAs, their potential value in cerebrovascular risk stratification, and their concordance with other vascular risk factors in community-dwelling elderly people. A total of 125 community-dwelling elderly subjects who underwent a brain MRI scan were selected from our prospectively collected imaging database. The morphological measures of LSAs were calculated on the vascular skeletons obtained by manual tracing, and the number of LSAs was counted. Additionally, imaging biomarkers of small vessel disease were evaluated, and the diameters of major cerebral arteries were measured. The effects of vascular risk factors on LSA morphometry, as well as the relationship between LSA measures and other imaging biomarkers, were investigated. We found that smokers had shorter (p = 0.04) and straighter LSAs (p < 0.01) compared to nonsmokers, and the presence of hypertension is associated with less tortuous LSAs (p = 0.03) in community-dwelling elderly. Moreover, the middle cerebral artery diameter was positively correlated with LSA count (r = 0.278, p = 0.025) and vessel tortuosity (r = 0.257, p = 0.04). The posterior cerebral artery diameter was positively correlated with vessel tortuosity and vessel length. Considering the scarcity of noninvasive methods for measuring small artery abnormalities in the brain, the LSA morphological measures may provide valuable information to better understand cerebral small vessel degeneration during aging.

BackgroundApolipoprotein E (APOE) ε2 is a protective genetic factor for Alzheimer’s disease (AD). However, the potential interaction effects between the APOE ε2 allele and disease status on the intrinsic brain activity remain elusive.MethodsWe identified 73 healthy control (HC) with APOE ε3/ε3, 61 mild cognitive impairment (MCI) subjects with APOE ε3/ε3, 24 HC with APOE ε2/ε3, and 10 MCI subjects with APOE ε2/ε3 from the ADNI database. All subjects underwent a resting-state functional MRI and Fluoro-deoxy-glucose positron emission tomography (FDG-PET). We used a fractional amplitude of low-frequency fluctuation (fALFF) to explore the spontaneous brain activity. Based on the mixed-effects analysis, we explored the interaction effects between the APOE ε2 allele versus disease status on brain activity and metabolism in a voxel-wise fashion (GRF corrected, p < 0.01), followed by post hoc two-sample t-tests (Bonferroni corrected, p < 0.05). We then investigated the relationship between the mean imaging metrics and cognitive abilities.ResultsThere are no significant differences in gender, age, or education among the four groups. The interaction effect on brain activity was located in the inferior parietal lobule (IPL). Post hoc analysis showed that APOE ε2/ε3 MCI had an increased IPL fALFF than APOE ε3/ε3 MCI. Regarding the APOE ε2 allele effects, we found that ε2 carriers had a decreased fALFF in the transverse temporal gyrus than non-carriers. Also, FDG-PET results showed a lower SUVR of the frontal lobe in APOE ε2 carriers than non-carriers. Furthermore, fALFF of IPL was correlated with the visuospatial function (r = −0.16, p < 0.05).ConclusionAPOE ε2 carriers might have a better brain reservation when coping with AD-related pathologies.

Background: The dilation of perivascular space (PVS) has been widely used to reflect brain degeneration in clinical brain imaging studies. However, PVS characteristics exhibit large differences in healthy subjects. Such variations need to be better addressed before PVS can be used to reflect pathological changes. In the present study, we aim to investigate the potential influence of several related factors on PVS dilation in healthy elderly subjects.Methods: One-hundred and three subjects (mean age = 59.5) were retrospectively included from a prospectively collected community cohort. Multi-modal high-resolution magnetic resonance imaging and cognitive assessments were performed on each subject. Machine-learning based segmentation methods were employed to quantify PVS volume and white matter hyperintensity (WMH) volume. Multiple regression analysis was performed to reveal the influence of demographic factors, vascular risk factors, intracranial volume (ICV), major brain artery diameters, and brain atrophy on PVS dilation.Results: Multiple regression analysis showed that age was positively associated with the basal ganglia (BG) (standardized beta = 0.227, p = 0.027) and deep white matter (standardized beta = 0.220, p = 0.029) PVS volume. Hypertension was positively associated with deep white matter PVS volume (standardized beta = 0.234, p = 0.017). Furthermore, we found that ICV was strongly associated with the deep white matter PVS volume (standardized beta = 0.354, p < 0.001) while the intracranial artery diameter was negatively associated with the deep white matter PVS volume (standardized beta = −0.213, p = 0.032).Conclusions: Intracranial volume has significant influence on deep white matter PVS volume. Future studies on PVS dilation should include ICV as an important covariate.

Background and Objective: The epidemic of coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has expanded from China throughout the world. This study aims to estimate the risk of disease progression of patients who have been confirmed with COVID-19.Methods: Meta-analysis was performed in existing literatures to identify risk factors associated with COVID-19 pneumonia progression. Patients with COVID-19 pneumonia were admitted to hospitals in Wuhan or Hangzhou were retrospectively enrolled. The risk prediction model and nomogram were developed from Wuhan cohort through logistic regression algorithm, and then validated in Hangzhou and Yinchuan cohorts.Results: A total of 270 patients admitted to hospital between Dec 30, 2019, and Mar 30, 2020, were retrospectively enrolled (Table 1). The development cohort (Wuhan cohort) included 87 (43%) men and 115 (57%) women, and the median age was 53 years old. Hangzhou validation cohort included 20 (48%) men and 22 (52%) women, and the median age was 59 years old. Yinchuan validation cohort included 12 (46%) men and 14 (54%) women, and the median age was 44 years old. The meta-analysis along with univariate logistic analysis in development cohort have shown that age, fever, diabetes, hypertension, CREA, BUN, CK, LDH, and neutrophil count were significantly associated with disease progression of COVID-19 pneumonia. The model and nomogram derived from development cohort show good performance in both development and validation cohorts.Conclusion: The severe COVID-19 pneumonia is associated with various types of risk factors including age, fever, comorbidities, and some laboratory examination indexes. The model integrated with these factors can help to evaluate the disease progression of COVID-19 pneumonia.

DNA methylation plays an important role in a wide range of developmental and physiological processes in plants. It is primarily catalyzed and regulated by cytosine-5 DNA methyltransferases (C5-MTases) and a group of DNA glycosylases that act as demethylases. To date, no genome-scale analysis of the two kiwifruit (Actinidia chinensis) families has been undertaken. In our study, nine C5-MTases and seven DNA demethylase genes were identified in the kiwifruit genome. Through selective evolution analysis, we found that there were gene duplications in C5-MTases and demethylases, which may have arisen during three genome doubling events followed by selection during evolution of kiwifruit. Expression analysis of DNA methylases (C5-MTases) and demethylases identified changes in transcripts of DNA methylation and demethylation genes during both vegetative and reproductive development. Moreover, we found that some members of the two methylase/demethylase families may also be involved in fruit ripening and the regulation of softening. Our results help to better understand the complex roles of methylation/demethylation in plants and provide a foundation for analyzing the role of DNA methylation modification in kiwifruit growth, development and ripening.

Recent small subcortical infarcts (RSSIs) can occur in different brain regions. Distinct etiologies might be involved for RSSIs in different locations and could further affect RSSI cavitation and functional outcomes. In this study, we aim to analyze the baseline clinical and imaging characteristics associated with the occurrence and cavitation of RSSIs in different locations. We retrospectively include patients who presented with RSSIs from a database for cerebral small vessel disease. Detailed information, including demographic, clinical, laboratory, and radiological data, were collected. We identify baseline RSSIs on diffusion-weighted images and divide them into brainstem, subcortical white matter, and basal ganglia region groups. Cavitation is evaluated on follow-up T2 fluid-attenuated inversion recovery (FLAIR) images. Statistical analysis is performed to determine factors associated with the occurrence and cavitation of RSSIs in different locations. We find that patients with brainstem RSSIs have a higher proportion of diabetes (64.1%) compared to patients with subcortical white matter (27.3%, P < 0.001) and basal ganglia region RSSIs (35.2%, P = 0.006) and have higher levels of HbA1c (7.20%) compared to patients with subcortical white matter (6.10%, P = 0.001) and basal ganglia region RSSIs (6.20%, P = 0.003). In addition, patients with brainstem RSSIs have higher NIHSS scores than patients with subcortical white matter RSSIs (2 vs 0, P = 0.001). Patients with subcortical white matter RSSIs have higher a white matter hyperintensity (WMH) burden compared to patients with basal ganglia region RSSIs (21.64 cm3 vs 11.10 cm3, P = 0.004). Follow-up analysis demonstrates that basal ganglia region RSSIs are less likely to cavitate than subcortical white matter RSSIs (61.4% vs 83.6%, P = 0.010), and contacting with WMH is associated with the cavitation of subcortical white matter RSSIs (OR: 101.760, P = 0.003). Our study demonstrates that RSSIs in different locations are associated with different clinical and imaging characteristics. Furthermore, cavitation of RSSIs might be affected by local lesion features and the surrounding environment rather than general demographic and clinical factors.

Background: The National Institute on Aging-Alzheimer’s Association (NIA-AA) has proposed a biological definition of Alzheimer’s disease (AD): individuals with both abnormal amyloid and tau biomarkers (A+T+) would be defined as AD. It remains unclear why different cognitive status is present in subjects with biological AD. Resting-state functional magnetic resonance imaging (rsfMRI) has provided an opportunity to reveal the brain activity patterns in a biologically-defined AD cohort. Accordingly, we aimed to investigate distinct brain activity patterns in subjects with existed AD pathology but in the different cognitive stages.Method: We selected individuals with AD pathology (A+T+) and healthy controls (HC, A−T−) based on the cerebrospinal fluid (CSF) biomarkers. According to the cognitive stage, we divided the A+T+ cohort into three groups: (1) preclinical AD; (2) prodromal AD; and (3) AD with dementia (d-AD). We compared spontaneous brain activity measured by a fractional amplitude of low-frequency fluctuation (fALFF) approach among four groups.Results: The analysis of covariance (ANCOVA) results showed significant differences in fALFF in the posterior cingulate cortex/precuneus (PCC/PCu). Further, compared to HC, we found increased fALFF values in the right inferior frontal gyrus (IFG) in the preclinical AD stage, whereas prodromal AD patients showed reduced fALFF in the bilateral precuneus, right middle frontal gyrus (MFG), right precentral gyrus, and postcentral gyrus. Within the d-AD group, both hyperactivity (right fusiform gyrus, right parahippocampal gyrus (PHG)/hippocampus, and inferior temporal gyrus) and hypoactivity (bilateral precuneus, left posterior cingulate cortex, left cuneus and superior occipital gyrus) were detected.Conclusion: We found the distinct brain activity patterns in different cognitive stages among the subjects defined as AD biologically. Our findings may be helpful in understanding mechanisms leading to cognitive changes in the AD pathophysiological process.

Background The biological diagnosis criteria of the Alzheimer’s disease (AD) suggests that previous work may misclassify the cognitive impairment caused by other factors into AD. Consequently, re-assessing the imaging profile of AD continuum is needed. Considering the high vulnerability of cortical association fibers, we aimed to elucidate the cortical demyelination process in the AD continuum biologically defined.Methods According to the biological diagnosis criteria, we determined the positive amyloid status (A+) as cerebrospinal fluid (CSF) amyloid1–42 < 192 pg/ml, Florbetapir Positron emission tomography (PET) composite standardized uptake value ratio (SUVR) >1.11. Also, the positive Tau status (T+) was determined as p-Tau181 > 23 pg/ml. Based on the cognitive characterization, we further categorized 252 subjects into 27 cognitively unimpaired with normal AD biomarkers (A−T−, controls), 49 preclinical AD (A+T+), 113 AD with mild cognitive impairment (MCI) (A+T+), and 63 AD dementia (A+T+). We estimated the intracortical myelin content used the T1- and T2-weighted (T1W/T2W) ratio mapping. To investigate the sensitivity of the ratio mapping, we also utilized well-validated AD imaging biomarkers as the reference, including gray matter volume and Fludeoxyglucose PET (FDG-PET). Based on the general linear model, we conducted the voxel-wise two-sample T-tests between the controls and each group in the AD continuum.Results Compared to the controls, the results showed that the preclinical AD patients exhibited decreased T1W/T2W ratio value in the right inferior parietal lobule (IPL); as the disease progresses, the prodromal AD patients demonstrated lower ratio value in bilateral IPL, with hippocampus (HP) atrophy. Lastly, the AD dementia patients exhibited decreased ratio value in bilateral IPL and hippocampus; also, we observed the bilateral temporal cortices atrophy and widespread decreased metabolism in the AD dementia patients. After corrected with gray volume, the results remained mostly unchanged.Conclusion Our study implied the decreased right IPL T1W/T2W ratio might represent early AD-related demyelination in disease continuum. Additionally, we demonstrated that the T1W/T2W ratio mapping is an easy-to-implement and sensitive metric to assess the intracortical myelin content in AD, particularly in the early stage.