Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. ...6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.
SUMMARY
Elucidating the biochemical and molecular basis of premature abscission in fruit crops should help develop strategies to enhance fruit set and yield. Here, we report that LcERF2 contributes ...to differential abscission rates and responses to ethylene in Litchi chinensis (litchi). Reduced LcERF2 expression in litchi was observed to reduce fruit abscission, concurrent with enhanced pedicel growth and increased levels of hexoses, particularly galactose, as well as pectin abundance in the cell wall. Ecoptic expression of LcERF2 in Arabidopsis thaliana caused enhanced petal abscission, together with retarded plant growth and reduced pedicel galactose and pectin contents. Transcriptome analysis indicated that LcERF2 modulates the expression of genes involved in cell wall modification. Yeast one‐hybrid, dual‐luciferase reporter and electrophoretic mobility shift assays all demonstrated that a UDP‐glucose‐4‐epimerase gene (LcUGE) was the direct downstream target of LcERF2. This result was further supported by a significant reduction in the expression of the A. thaliana homolog AtUGE2‐4 in response to LcERF2 overexpression. Significantly reduced pedicel diameter and enhanced litchi fruit abscission were observed in response to LcUGE silencing. We conclude that LcERF2 mediates fruit abscission by orchestrating cell wall metabolism, and thus pedicel growth, in part by repressing the expression of LcUGE.
Significance Statement
This study shed light upon the critical role of LcERF2 in regulating organ abscission by repressing the expression of LcUGE and thus inhibiting cell wall biosynthesis and organ growth. In addition, our work revealed the role of LcUGE in pedicel development and fruit abscission in litchi, and demonstrated that LcERF2 repressed the expression of LcUGE by binding to a region 800–850 bp upstream.
Although numerous studies on the impacts of climate change on biodiversity have been published, only a handful are focused on the intraspecific level or consider population‐level models (separate ...models per population). We endeavored to fill this knowledge gap relative to the Qinghai‐Tibetan plateau (QTP) by combining species distribution modeling (SDMs) with population genetics (i.e., population‐level models) and phylogenetic methods (i.e., phylogenetic tree reconstruction and phylogenetic diversity analyses). We applied our models to 11 endemic and widely distributed herpetofauna species inhabiting high elevations in the QTP. We aimed to determine the influence of environmental heterogeneity on species’ responses to climate change, the magnitude of climate‐change impacts on intraspecific diversity, and the relationship between species range loss and intraspecific diversity losses under 2 shared socioeconomic pathways (SSP245 and SSP585) and 3 future periods (2050s, 2070s, and 2090s). The effects of global climatic change were more pronounced at the intraspecific level (22% of haplotypes lost and 36% of populations lost) than the morphospecies level in the SSP585 climate change scenario. Maintenance of genetic diversity was in general determined by a combination of factors including range changes, species genetic structure, and the part of the range predicted to be lost. This is owing to the fact that the loss and survival of populations were observed in species irrespective of the predicted range changes (contraction or expansion). In the southeast (mountainous regions), climate change had less of an effect on range size (>100% in 3 species) than in central and northern QTP plateau regions (range size <100% in all species). This may be attributed to environmental heterogeneity, which provided pockets of suitable climate in the southeast, whereas ecosystems in the north and central regions were homogeneous. Generally, our results imply that mountainous regions with high environmental heterogeneity and high genetic diversity may buffer the adverse impacts of climate change on species distribution and intraspecific diversity. Therefore, genetic structure and characteristics of the ecosystem may be crucial for conservation under climate change.
Impactos del cambio climático sobre la diversidad de herpetofauna en la meseta Qinghai‐Tíbet
Región
Aunque se han publicado numerosos estudios sobre los impactos del cambio climática en la biodiversidad, son muy pocos los que se enfocan en el nivel intraespecífico o que consideran modelos a nivel poblacional (modelos separados por población). Intentamos cerrar este vacío de conocimiento en relación con la meseta Qinghai‐Tíbet (MQT) con la combinación entre modelos de distribución de especies (MDE) y genética poblacional (modelos a nivel poblacional) y métodos filogenéticos (reconstrucción de árboles filogenéticos y análisis de diversidad filogenética). Aplicamos nuestros modelos a once especies endémicas de herpetofauna con distribución amplia en las elevaciones más altas de la MQT. Nos planteamos determinar la influencia de la heterogeneidad de las especies sobre la respuesta de las especies al cambio climático, la magnitud de los impactos del cambio climático sobre la diversidad intraespecífica y la relación entre la pérdida de distribución de la especie y las pérdidas de diversidad intraespecífica bajo dos vías socioeconómicas (SSP245 y SSP585) y tres periodos del futuro (2050s, 2070s y 2090s). Los efectos del cambio climático global fueron más pronunciados a nivel intraespecífico (22% de pérdida en los haplotipos y 36% en las poblaciones) que al nivel morfoespecie en el escenario de cambio climático SSP585. El mantenimiento de la diversidad genética casi siempre estuvo determinado por una combinación de factores que incluyen cambios en la distribución, estructura genética de las especies y la parte de la distribución que se pronosticó se perdería. Esto se debe a que observamos la pérdida y supervivencia de las poblaciones sin importar los cambios pronosticados en la distribución (contracción o expansión). En las regiones montañosas del sureste, el cambio climático tuvo un efecto menor sobre la distribución (>100% en tres especies) comparado con las regiones de la meseta central y del norte de la MQT (distribución <100% en todas las especies). Esto puede atribuirse a la heterogeneidad ambiental, la cual proporciona recovecos de clima adecuado en el sureste, mientras que los ecosistemas en las regiones central y norte fueron homogéneos. De manera general, nuestros resultados implican que las regiones montañosas con una elevada heterogeneidad ambiental y una gran diversidad genética podrían reducir los impactos adversos del cambio climático sobre la distribución de las especies y la diversidad intraespecífica. Por lo tanto, la estructura genética y las características del ecosistema pueden ser cruciales para conservar bajo el cambio climático.
【摘要】
尽管已有大量有关气候变化对生物多样性影响的研究发表, 但只有少数研究考虑种下或种群水平的模型。我们将物种分布模型(SDMs)与种群遗传学和系统发生学方法相结合, 填补青藏高原地区(QTP)在这一方面的研究空白。我们对11种栖息在青藏高原特有且分布广泛的两栖爬行动物进行了模型分析, 探究环境异质性对物种响应气候变化的影响、气候变化对种内多样性的影响程度、以及在SSP245和SSP585两种情景下, 未来(2050年、2070年和2090年)物种分布范围丧失与种内多样性丧失之间的关系。结果显示, 在SSP585气候变化情景中, 在种下有22%的单倍型和36%的种群将会丢失, 全球气候变化对种内多样性的影响比种间更为明显。遗传多样性是否能够维持一般由多种因素共同决定, 包括分布区的变化、物种遗传结构以及预测丢失的分布区。在青藏高原东南部山区, 气候变化对物种分布范围大小的影响(有3个物种的分布范围扩张)小于青藏高原北部和中部地区(所有物种的分布范围均缩小), 主要原因可能是东南部环境异质性更高, 物种可以选择较为合适的生境, 而北部和中部地区环境则趋于同质化。本研究结果表明, 环境异质性高、遗传多样性高的山区可以缓冲气候变化对物种分布和种内多样性的不利影响。因此, 生态系统的遗传结构和特征对于气候变化下的多样性保护至关重要。
Reduced
F-fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism was recognized as a biomarker of neurodegeneration in the recently proposed ATN framework for Alzheimer's disease ...(AD) biological definition. However, accumulating evidence suggested it is an independent biomarker, which is denoted as "F" in the very study.
A total of 551 A+T+ individuals from the Alzheimer's Disease Neuroimaging Initiative database were recruited and then further divided into four groups based on the biomarker positivity as 132 A+T+N-F-, 102 A+T+N-F+, 113 A+T+N+F-, and 204 A+T+N+F+. Frequency distributions of the groups were compared, as well as the clinical progression measured by the longitudinal changes in cognition and brain structure, and mild cognitive impairment (MCI) to AD dementia conversion between every pair of F+ and F- groups.
The prevalence of A+T+N+F+ profile was 66.24% in clinically diagnosed AD dementia patients; similarly, the majority of individuals with reduced FDG-PET were AD dementia subjects. Among the 551 individuals that included, 537 had at least one follow-up (varied from 1 to 8 years). Individuals in F+ groups performed worse and dropped faster in Mini-Mental State Examination scale and had faster shrinking middle temporal lobe than those in F- groups (all p < 0.05). Moreover, in MCI patients, reduced FDG-PET exerted 2.47 to 4.08-fold risk of AD dementia progression compared with those without significantly impaired FDG-PET (both p < 0.001).
Based on the analyses, separating FDG-PET from "N" biomarker to build the ATN(F) system is necessary and well-founded. The analysis from this study could be a complement to the original ATN framework for AD's biological definition.
Diseases of the stomach, including gastric cancer and peptic ulcer, are the most common digestive diseases. It is impossible to visualize the entire stomach with the passive capsule currently used in ...practice because of the large size of the gastric cavity. A magnetically controlled capsule endoscopy (MCE) system has been designed to explore the stomach. We performed a prospective study to compare the accuracy of detection of gastric focal lesions by MCE vs conventional gastroscopy (the standard method).
We performed a multicenter blinded study comparing MCE with conventional gastroscopy in 350 patients (mean age, 46.6 y), with upper abdominal complaints scheduled to undergo gastroscopy at a tertiary center in China from August 2014 through December 2014. All patients underwent MCE, followed by conventional gastroscopy 2 hours later, without sedation. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of detection of gastric focal lesions by MCE, using gastroscopy as the standard.
MCE detected gastric focal lesions in the whole stomach with 90.4% sensitivity (95% confidence interval CI, 84.7%–96.1%), 94.7% specificity (95% CI, 91.9%–97.5%), a positive predictive value of 87.9% (95% CI, 81.7%–94.0%), a negative predictive value of 95.9% (95% CI, 93.4%–98.4%), and 93.4% accuracy (95% CI, 90.83%–96.02%). MCE detected focal lesions in the upper stomach (cardia, fundus, and body) with 90.2% sensitivity (95% CI, 82.0%–98.4%) and 96.7% specificity (95% CI, 94.4%–98.9%). MCE detected focal lesions in the lower stomach (angulus, antrum, and pylorus) with 90.6% sensitivity (95% CI, 82.7%–98.4%) and 97.9% specificity (95% CI, 96.1%–99.7%). MCE detected 1 advanced gastric carcinoma, 2 malignant lymphomas, and 1 early stage gastric tumor. MCE did not miss any lesions of significance (including tumors or large ulcers). Among the 350 patients, 5 reported 9 adverse events (1.4%) and 335 preferred MCE over gastroscopy (95.7%).
MCE detects focal lesions in the upper and lower stomach with comparable accuracy with conventional gastroscopy. MCE is preferred by almost all patients, compared with gastroscopy, and can be used to screen gastric diseases without sedation. Clinicaltrials.gov number: NCT02219529.
Stroke is the most common cerebrovascular disease, the second leading cause of death behind heart disease and is a major cause of long-term disability worldwide. Currently, systemic immunomodulatory ...therapy based on intravenous cells is attracting attention. The immune response to acute stroke is a major factor in cerebral ischaemia (CI) pathobiology and outcomes. Over the past decade, the significant contribution of the spleen to ischaemic stroke has gained considerable attention in stroke research. The changes in the spleen after stroke are mainly reflected in morphology, immune cells and cytokines, and these changes are closely related to the stroke outcomes. Autonomic nervous system (ANS) activation, release of central nervous system (CNS) antigens and chemokine/chemokine receptor interactions have been documented to be essential for efficient brain-spleen cross-talk after stroke. In various experimental models, human umbilical cord blood cells (hUCBs), haematopoietic stem cells (HSCs), bone marrow stem cells (BMSCs), human amnion epithelial cells (hAECs), neural stem cells (NSCs) and multipotent adult progenitor cells (MAPCs) have been shown to reduce the neurological damage caused by stroke. The different effects of these cell types on the interleukin (IL)-10, interferon (IFN), and cholinergic anti-inflammatory pathways in the spleen after stroke may promote the development of new cell therapy targets and strategies. The spleen will become a potential target of various stem cell therapies for stroke represented by MAPC treatment.
To study the clinical features of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
A retrospective analysis was performed for the clinical data of 13 children ...with SARS-CoV-2 infection who hospitalized in a Changsha hospital.
All 13 children had the disease onset due to family aggregation. Of the 13 children, 2 had no symptoms, and the other 11 children had the clinical manifestations of fever, cough, pharyngeal discomfort, abdominal pain, diarrhea, convulsions, or vomiting. As for clinical typing, 7 had mild type, 5 had common type, and 1 had severe type. The median duration of fever was 2 days in 6 children. All 13 children had normal levels of peripheral blood lymphocyte counts, immunoglobulins, CD4, CD8, and interleukin-6. The median time to clearance of SARS-CoV-2 was 13 days in the nasopharyngeal swabs of the 13 children. Three children presented false negatives for RT-PCR of SARS-CoV-2. SARS-CoV-2 RNA remained detectable in stools for 12 days after the nasopharyngea
Anthocyanins generate the red color in the pericarp of Litchi chinensis. UDP‐glucose: flavonoid 3‐O‐glycosyltransferase (UFGT, EC. 2.4.1.91) stabilizes anthocyanidin by attaching sugar moieties to ...the anthocyanin aglycone. In this study, the function of an UFGT gene involved in the biosynthesis of anthocyanin was verified through heterologous expression and virus‐induced gene silencing assays. A strong positive correlation between UFGT activity and anthocyanin accumulation capacity was observed in the pericarp of 15 cultivars. Four putative flavonoid 3‐O‐glycosyltransferase‐like genes, designated as LcUFGT1 to LcUFGT4, were identified in the pericarp of litchi. Among the four UFGT gene members, only LcUFGT1 can use cyanidin as its substrate. The expression of LcUFGT1 was parallel with developmental anthocyanin accumulation, and the heterologously expressed protein of LcUFGT1 displayed catalytic activities in the formation of anthocyanin. The LcUFGT1 over‐expression tobacco had darker petals and pigmented filaments and calyxes resulting from higher anthocyanin accumulations compared with non‐transformed tobacco. In the pericarp with LcUFGT1 suppressed by virus‐induced gene silencing, pigmentation was retarded, which was well correlated with the reduced‐LcUFGT1 transcriptional activity. These results suggested that the glycosylation‐related gene LcUFGT1 plays a critical role in red color formation in the pericarp of litchi.
Introduction
Plasma markers have been reported to be associated with brain amyloid burden, tau pathology, or neurodegeneration. We aimed to evaluate whether plasma biomarker profiles could predict ...Alzheimer's disease (AD) pathology and clinical progression in older adults without dementia.
Methods
Cross‐sectional and longitudinal data of participants enrolled in this study were from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Plasma amyloid beta (Aβ)1‐42/Aβ1‐40 ratio was selected as the marker for amyloid pathology, p‐tau181 for tau pathology, and neurofilament light for neurodegeneration. Cut‐offs for these plasma markers were calculated with well‐established positron emission tomography and structural imaging biomarkers as reference. Older adults without dementia were categorized into eight groups at baseline by plasma amyloid/tau/neurodegeneration (A/T/N) cut‐offs. Clinical progression was analyzed using linear mixed‐effects models and Cox proportional hazard models.
Results
A total of 183 participants (97 cognitively normal CN subjects and 86 patients with mild cognitive impairment MCI; mean age 72.6 years, and 48.1% men) were included. Participants with A+ had significantly higher proportions of apolipoprotein E (APOE) gene ɛ4 carriers than those with A–. Brain atrophy was observed in all groups of CN, whereas cognition decline was obvious in the A+T+N+ group. Compared to A–T–N–, MCI patients with A+T+N+ had faster cognition worsening and faster brain atrophy. In the whole cohort, A+T+N+ and A+T+N– participants were at higher risk of clinical progression.
Discussion
Plasma A/T/N biomarker profiles may predict AD pathology and clinical progression, indicating a potential role for plasma biomarkers in clinical trials. More research is warranted to develop a robust plasma AD framework.
Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy ...induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆-
-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.
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