CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.

Although tumor-intrinsic fatty acid ß-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.

Transcription factor CmHSFA4-CmMYBS3 complex enhances salt tolerance in chrysanthemum by repressing CmMYB121 expression.

Excessive soil salinity not only hampers plant growth and development but can also lead to plant death. Previously, we found that heat shock factor A4 (CmHSFA4) enhances the tolerance of chrysanthemum (Chrysanthemum morifolium) to salt. However, the underlying molecular mechanism remains unclear. In this study, we identified a candidate MYB transcription factor, CmMYB121, which responded to salt stress. We observed that the CmMYB121 transcription is suppressed by CmHSFA4. Moreover, overexpression of CmMYB121 exacerbated chrysanthemum sensitivity to salt stress. CmHSFA4 directly bound to the promoter of CmMYB121 at the heat shock element (HSE). Protein-protein interaction assays identified an interaction between CmHSFA4 and CmMYBS3, a transcriptional repressor, and recruited the corepressor TOPLESS (CmTPL) to inhibit CmMYB121 transcription by impairing the H3 and H4 histone acetylation levels of CmMYB121. Our study demonstrated that a CmHSFA4-CmMYBS3-CmTPL complex modulates CmMYB121 expression, consequently regulating the tolerance of chrysanthemum to salt. The findings shed light on the responses of plants to salt stress.

A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Intratumoral injection of schwannoma with attenuated Salmonella typhimurium induces antitumor immunity and controls tumor growth.

Schwannomas are slow-growing benign neoplasms that develop throughout the body causing pain, sensory/motor dysfunction, and death. Because bacterial immunotherapy has been used in the treatment of some malignant neoplasms, we evaluated attenuated Salmonella typhimurium strains as immunotherapies for benign murine schwannomas. Several bacterial strains were tested, including VNP20009, a highly attenuated strain that was previously shown to be safe in human subjects with advanced malignant neoplasms, and a VNP20009 mutant that was altered in motility and other properties that included adherence and invasion of cultured mammalian cells. VNP20009 controlled tumor growth in two murine schwannoma models and induced changes in cytokine and immune effector cell profiles that were consistent with induction of enhanced innate and adaptive host immune responses compared with controls. Intratumoral (i.t.) injection of S. typhimurium led to tumor cell apoptosis, decreased tumor angiogenesis, and lower growth of the injected schwannoma tumors. Invasive VNP20009 was significantly more efficacious than was a noninvasive derivative in controlling the growth of injected tumors. Bacterial treatment apparently induced systemic antitumor immunity in that the growth of rechallenge schwannomas implanted following primary bacterial treatment was also reduced. Checkpoint programmed death-1 (PD-1) blockade induced by systemic administration of anti-PD-1 antibodies controlled tumor growth to the same degree as i.t. injection of S. typhimurium, and together, these two therapies had an additive effect on suppressing schwannoma growth. These experiments represent validation of a bacterial therapy for a benign neoplasm and support development of S. typhimurium VNP20009, potentially in combination with PD-1 inhibition, as a schwannoma immunotherapy.

Association of improved air quality with lower dementia risk in older women.

Late-life ambient air pollution is a risk factor for brain aging, but it remains unknown if improved air quality (AQ) lowers dementia risk. We studied a geographically diverse cohort of older women dementia free at baseline in 2008 to 2012 (n = 2,239, aged 74 to 92). Incident dementia was centrally adjudicated annually. Yearly mean concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated using regionalized national universal kriging models and averaged over the 3-y period before baseline (recent exposure) and 10 y earlier (remote exposure). Reduction from remote to recent exposures was used as the indicator of improved AQ. Cox proportional hazard ratios (HRs) for dementia risk associated with AQ measures were estimated, adjusting for sociodemographic, lifestyle, and clinical characteristics. We identified 398 dementia cases during follow up (median = 6.1 y). PM2.5 and NO2 reduced significantly over the 10 y before baseline. Larger AQ improvement was associated with reduced dementia risks (HRPM2.5 0.80 per 1.78 µg/m3, 95% CI 0.71-0.91; HRNO2 0.80 per 3.91 parts per billion, 95% CI 0.71-0.90), equivalent to the lower risk observed in women 2.4 y younger at baseline. Higher PM2.5 at baseline was associated with higher dementia risk (HRPM2.5 1.16 per 2.90 µg/m3, 95% CI 0.98-1.38), but the lower dementia risk associated with improved AQ remained after further adjusting for recent exposure. The observed associations did not substantially differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. Long-term AQ improvement in late life was associated with lower dementia risk in older women.

PENCIL imaging: A novel approach for neuromelanin sensitive MRI in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is widely used for NM visualization but has limitations in brain coverage and scan time. This study aimed to develop a new approach called Proton-density Enhanced Neuromelanin Contrast in Low flip angle gradient echo (PENCIL) imaging to visualize NM in the SN. METHODS: This study included 30 PD subjects and 50 healthy controls (HCs) scanned at 3T. PENCIL and MTC images were acquired. NM volume in the SN pars compacta (SNpc), normalized image contrast (Cnorm), and contrast-to-noise ratio (CNR) were calculated. The change of NM volume in the SNpc with age was analyzed using the HC data. A group analysis compared differences between PD subjects and HCs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculations were used to evaluate the diagnostic performance of NM volume and CNR in the SNpc. RESULTS: PENCIL provided similar visualization and structural information of NM compared to MTC. In HCs, PENCIL showed higher NM volume in the SNpc than MTC, but this difference was not observed in PD subjects. PENCIL had higher CNR, while MTC had higher Cnorm. Both methods revealed a similar pattern of NM volume in SNpc changes with age. There were no significant differences in AUCs between NM volume in SNpc measured by PENCIL and MTC. Both methods exhibited comparable diagnostic performance in this regard. CONCLUSIONS: PENCIL imaging provided improved CNR compared to MTC and showed similar diagnostic performance for differentiating PD subjects from HCs. The major advantage is PENCIL has rapid whole-brain coverage and, when using STAGE imaging, offers a one-stop quantitative assessment of tissue properties.

Liberating C-H Bond Activation: Achieving 56% Quantum Efficiency in Photocatalytic Cyclohexane Dehydrogenation.

The technology of liquid organic hydrogen carriers presents great promise for large-scale hydrogen storage. Nevertheless, the activation of inert C(sp3)-H bonds in hydrocarbon carriers poses formidable challenges, resulting in a sluggish dehydrogenation process and necessitating high operating temperatures. Here, we break the shackles of C-H bond activation under visible light irradiation by fabricating subnanometer Pt clusters on defective Ce-Zr solid solutions. We achieved an unprecedented hydrogen production rate of 2601 mmol gcat.-1 h-1 (turnover frequency >50,000 molH2 molPt-1 h-1) from cyclohexane, surpassing the most advanced thermo- and photocatalysts. By optimizing the temperature-dominated hydrogen transfer process, achievable by harnessing hitherto wasted infrared light in sunlight, an astonishing 56% apparent quantum efficiency and a 5.2% solar-to-hydrogen efficiency are attained at 353 K. Our research stands as one of the most effective photocatalytic processes to date, holding profound practical significance in the utilization of solar energy and the exploitation of alkanes.

Chrysanthemum (Chrysanthemum morifolium) CmHRE2-like negatively regulates the resistance of chrysanthemum to the aphid (Macrosiphoniella sanborni).

BACKGROUND: The growth and ornamental value of chrysanthemums are frequently hindered by aphid attacks. The ethylene-responsive factor (ERF) gene family is pivotal in responding to biotic stress, including insect stress. However, to date, little is known regarding the involvement of ERF transcription factors (TFs) in the response of chrysanthemum to aphids. RESULTS: In the present study, CmHRE2-like from chrysanthemum (Chrysanthemum morifolium), a transcription activator that localizes mainly to the nucleus, was cloned. Expression is induced by aphid infestation. Overexpression of CmHRE2-like in chrysanthemum mediated its susceptibility to aphids, whereas CmHRE2-like-SRDX dominant repressor transgenic plants enhanced the resistance of chrysanthemum to aphids, suggesting that CmHRE2-like contributes to the susceptibility of chrysanthemum to aphids. The flavonoids in CmHRE2-like-overexpression plants were decreased by 29% and 28% in two different lines, whereas they were increased by 42% and 29% in CmHRE2-like-SRDX dominant repressor transgenic plants. The expression of Chrysanthemum-chalcone-synthase gene(CmCHS), chalcone isomerase gene (CmCHI), and flavonoid 3'-hydroxylase gene(CmF3'H) was downregulated in CmHRE2-like overexpression plants and upregulated in CmHRE2-like-SRDX dominant repressor transgenic plants, suggesting that CmHRE2-like regulates the resistance of chrysanthemum to aphids partially through the regulation of flavonoid biosynthesis. CONCLUSION: CmHRE2-like was a key gene regulating the vulnerability of chrysanthemum to aphids. This study offers fresh perspectives on the molecular mechanisms of chrysanthemum-aphid interactions and may bear practical significance for developing new strategies to manage aphid infestation in chrysanthemums.

The causal relationship between autoimmune thyroid disorders and telomere length: A Mendelian randomization and colocalization study.

This study aimed to evaluate whether there is a causal relationship between autoimmune thyroid disorders (AITDs) and telomere length (TL) in the European population and whether there is reverse causality. In this study, Mendelian randomization (MR) and colocalization analysis were conducted to assess the potential causal relationship between AITDs and TL using summary statistics from large-scale genome-wide association studies, followed by analysis of the relationship between TL and thyroid stimulating hormone and free thyroxine (FT4) to help interpret the findings. The inverse variance weighted (IVW) method was used to estimate the causal estimates. The weighted median, MR-Egger and leave-one-out methods were used as sensitivity analyses. The IVW method results showed a significant causal relationship between autoimmune hyperthyroidism and TL (ß = -1.93 × 10-2 ; p = 4.54 × 10-5 ). There was no causal relationship between autoimmune hypothyroidism and TL (ß = -3.99 × 10-3 ; p = 0.324). The results of the reverse MR analysis showed that genetically TL had a significant causal relationship on autoimmune hyperthyroidism (IVW: odds ratio (OR) = 0.49; p = 2.83 × 10-4 ) and autoimmune hypothyroidism (IVW: OR = 0.86; p = 7.46 × 10-3 ). Both horizontal pleiotropy and heterogeneity tests indicated the validity of our bidirectional MR study. Finally, colocalization analysis suggested that there were shared causal variants between autoimmune hyperthyroidism and TL, further highlighting the robustness of the results. In conclusion, autoimmune hyperthyroidism may accelerate telomere attrition, and telomere attrition is a causal factor for AITDs.

Assessment of Lung Nodule Detection and Lung CT Screening Reporting and Data System Classification Using Zero Echo Time Pulmonary MRI.

BACKGROUND: The detection rate of lung nodules has increased considerably with CT as the primary method of examination, and the repeated CT examinations at 3 months, 6 months or annually, based on nodule characteristics, have increased the radiation exposure of patients. So, it is urgent to explore a radiation-free MRI examination method that can effectively address the challenges posed by low proton density and magnetic field inhomogeneities. PURPOSE: To evaluate the potential of zero echo time (ZTE) MRI in lung nodule detection and lung CT screening reporting and data system (lung-RADS) classification, and to explore the value of ZTE-MRI in the assessment of lung nodules. STUDY TYPE: Prospective. POPULATION: 54 patients, including 21 men and 33 women. FIELD STRENGTH/SEQUENCE: Chest CT using a 16-slice scanner and ZTE-MRI at 3.0T based on fast gradient echo. ASSESSMENT: Nodule type (ground-glass nodules, part-solid nodules, and solid nodules), lung-RADS classification, and nodule diameter (manual measurement) on CT and ZTE-MRI images were recorded. STATISTICAL TESTS: The percent of concordant cases, Kappa value, intraclass correlation coefficient (ICC), Wilcoxon signed-rank test, Spearman's correlation, and Bland-Altman. The p-value <0.05 is considered significant. RESULTS: A total of 54 patients (age, 54.8 ± 11.9 years; 21 men) with 63 nodules were enrolled. Compared with CT, the total nodule detection rate of ZTE-MRI was 85.7%. The intermodality agreement of ZTE-MRI and CT lung nodules type evaluation was substantial (Kappa = 0.761), and the intermodality agreement of ZTE-MRI and CT lung-RADS classification was moderate (Kappa = 0.592). The diameter measurements between ZTE-MRI and CT showed no significant difference and demonstrated a high degree of interobserver (ICC = 0.997-0.999) and intermodality (ICC = 0.956-0.985) agreements. DATA CONCLUSION: The measurement of nodule diameter by pulmonary ZTE-MRI is similar to that by CT, but the ability of lung-RADS to classify nodes from MRI images still requires further research. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Interferon-mediated repression of miR-324-5p potentiates necroptosis to facilitate antiviral defense.

Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3'UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.

Association Between Self- and Proxy-Reported Depression and Quality of Life in Mild-Moderate Alzheimer's Disease.

OBJECTIVE: Prior studies have reported an association between depression and quality of life (QOL) in Alzheimer's disease (AD), but the effect of self- versus proxy rating of mood and QOL has not been described. DESIGN: In this secondary analysis of data from a cohort study, the authors used a linear mixed-effects model to determine if the association between depression and QOL is affected by whether both measures are assessed by the same member of the patient-caregiver dyad. SETTING: Participants and caregiver informants were recruited from 10 California Alzheimer Disease Centers. PARTICIPANTS: A total of 137 participants with mild-to-moderate Alzheimer's disease and their caregivers. MEASUREMENTS: Self- and proxy-rated scores on both the Geriatric Depression Scale (GDS) and the Quality of Life in Alzheimer's Disease scale (QoL-AD). Multivariable linear mixed-effects models were used to estimate the association between depression and QOL. RESULTS: Results of the multivariable linear mixed-effects models showed a significant association between self-rated QoL-AD and self-rated (B = -0.49, p <0.0001) but not proxy-rated GDS (B = -0.07, p = 0.19) after adjusting for confounders. Likewise, there was a significant association between proxy-rated QoL-AD and proxy-rated GDS (B = -0.48, p <0.0001) but not self-rated GDS (B = 0.05, p = 0.36). CONCLUSION: Depression was associated with QOL in AD over short-term longitudinal follow-up, but the association was not statistically significant if both instruments are not administered to the same member of the patient-caregiver dyad. The choice of self- versus proxy-reported QOL should be intentionally considered in future studies as it may influence reported outcomes.

Structure-Guided Discovery of Diverse Cytotoxic Dimeric Xanthones/Chromanones from Penicillium chrysogenum C-7-2-1 and Their Interconversion Properties.

Xanthone-chromanone homo- or heterodimers are regarded as a novel class of topoisomerase (Topo) inhibitors; however, limited information about these compounds is currently available. Here, 14 new (1-14) and 6 known tetrahydroxanthone chromanone homo- and heterodimers (15-20) are reported as isolated from Penicillium chrysogenum C-7-2-1. Their structures and absolute configurations were unambiguously demonstrated by a combination of spectroscopic data, single-crystal X-ray diffraction, modified Mosher's method, and electronic circular dichroism analyses. Plausible biosynthetic pathways are proposed. For the first time, it was discovered that tetrahydroxanthones can convert to chromanones in water, whereas chromone dimerization does not show this property. Among them, compounds 5, 7, 8, and 16 exhibited significant cytotoxicity against H23 cell line with IC50 values of 6.9, 6.4, 3.9, and 2.6 µM, respectively.

Efficacy and safety of acupressure in nausea and vomiting during pregnancy: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of acupressure on nausea and vomiting during pregnancy. METHODS: PubMed, Embase, Springer, Web of Science, and the Cochrane Library were searched for all randomized controlled trials (RCT) of treating nausea and vomiting during pregnancy by acupressure from the inception date of database to July 31st, 2023. Study selection, data extraction, and risk of bias assessment were conducted independently by researchers. The methodological quality of included studies was evaluated by the Cochrane Collaboration's bias risk assessment tool, meta-analysis by Stata 17.0 software, and publication bias by Begg's test. RESULTS: A total of 11 RCTs involving 1378 pregnant women were included in this review, which was assessed to be moderate quality. 10 RCTs involving 1298 pregnant women were assessed for the meta-analysis. The results revealed that acupressure showed significant difference on improvement in symptom score compared with sham acupressure (pooled MD, - 1.33; 95%CI [- 2.06, - 0.61]; P < 0.001) or control group (pooled MD, - 0.73; 95%CI [- 1.08, - 0.39]; P < 0.001), and incidence of effective rate compared with sham acupressure group (pooled RR, 1.78; 95%CI [1.03, 3.07]; P = 0.039). However, no statistical significance was found between acupressure and control group (pooled RR, 4.53; 95%CI [0.67, 30.48]; P = 0.120) on effective rate. On comparing acupressure with sham acupressure, there was no beneficial effect on preventing nausea and vomiting during pregnancy (pooled RR, 0.83; 95%CI [0.50, 1.38]; P = 0.476), shortening the duration of hospital stay (pooled MD, - 0.78; 95%CI [- 1.98, 0.41]; P = 0.199) and improving patient satisfaction (pooled RR, 1.36; 95%CI [0.47, 3.91]; P = 0.570). Begg's test did not reveal any publication bias. Only one RCT reported minimal acupressure-related adverse events. CONCLUSION: Acupressure may have potential favorable or encouraging effect on treating nausea and vomiting during pregnancy, but strong supportive data are not yet available. Well-designed and large-scale RCTs should be conducted for assessing and confirming the efficacy and safety of acupressure in nausea and vomiting during pregnancy.

20-year depressive symptoms, dementia, and structural neuropathology in older women.

INTRODUCTION: The course of depressive symptoms and dementia risk is unclear, as are potential structural neuropathological common causes. METHODS: Utilizing joint latent class mixture models, we identified longitudinal trajectories of annually assessed depressive symptoms and dementia risk over 21 years in 957 older women (baseline age 72.7 years old) from the Women's Health Initiative Memory Study. In a subsample of 569 women who underwent structural magnetic resonance imaging, we examined whether estimates of cerebrovascular disease and Alzheimer's disease (AD)-related neurodegeneration were associated with identified trajectories. RESULTS: Five trajectories of depressive symptoms and dementia risk were identified. Compared to women with minimal symptoms, women who reported mild and stable and emerging depressive symptoms were at the highest risk of developing dementia and had more cerebrovascular disease and AD-related neurodegeneration. DISCUSSION: There are heterogeneous profiles of depressive symptoms and dementia risk. Common neuropathological factors may contribute to both depression and dementia. Highlights The progression of depressive symptoms and concurrent dementia risk is heterogeneous. Emerging depressive symptoms may be a prodromal symptom of dementia. Cerebrovascular disease and AD are potentially shared neuropathological factors.

Chondroitin Sulfate Proteoglycan 4 Provides New Treatment Approach to Preventing Peritoneal Dissemination in Ovarian Cancer.

Most epithelial ovarian cancer (EOC) patients are diagnosed with peritoneal dissemination. Cellular interactions are an important aspect of EOC cells when they detach from the primary site of the ovary. However, the mechanism remains underexplored. Our study aimed to reveal the role of chondroitin sulfate proteoglycan 4 (CSPG4) in EOC with a major focus on cell-cell interactions. We examined the expression of CSPG4 in clinical samples and cell lines of EOC. The proliferation, migration, and invasion abilities of the CSPG4 knockdown cells were assessed. We also assessed the role of CSPG4 in spheroid formation and peritoneal metastasis in an in vivo model using sh-CSPG4 EOC cell lines. Of the clinical samples, 23 (44.2%) samples expressed CSPG4. CSPG4 was associated with a worse prognosis in patients with advanced EOC. Among the EOC cell lines, aggressive cell lines, including ES2, expressed CSPG4. When CSPG4 was knocked down using siRNA or shRNA, the cell proliferation, migration, and invasion abilities were significantly decreased compared to the control cells. Proteomic analyses showed changes in the expression of proteins related to the cell movement pathways. Spheroid formation was significantly inhibited when CSPG4 was inhibited. The number of nodules and the tumor burden of the omentum were significantly decreased in the sh-CSPG4 mouse models. In the peritoneal wash fluid from mice injected with sh-CSPG4 EOC cells, significantly fewer spheroids were present. Reduced CSPG4 expression was observed in lymphoid enhancer-binding factor 1-inhibited cells. CSPG4 is associated with aggressive features of EOC and poor prognosis. CSPG4 could be a new treatment target for blocking peritoneal metastasis by inhibiting spheroid formation.

Current status of secondary metabolite pathways linked to their related biosynthetic gene clusters in Aspergillus section Nigri.

Covering: up to the end of 2021Aspergilli are biosynthetically 'talented' micro-organisms and therefore the natural products community has continually been interested in the wealth of biosynthetic gene clusters (BGCs) encoding numerous secondary metabolites related to these fungi. With the rapid increase in sequenced fungal genomes combined with the continuous development of bioinformatics tools such as antiSMASH, linking new structures to unknown BGCs has become much easier when taking retro-biosynthetic considerations into account. On the other hand, in most cases it is not as straightforward to prove proposed biosynthetic pathways due to the lack of implemented genetic tools in a given fungal species. As a result, very few secondary metabolite biosynthetic pathways have been characterized even amongst some of the most well studied Aspergillus spp., section Nigri (black aspergilli). This review will cover all known biosynthetic compound families and their structural diversity known from black aspergilli. We have logically divided this into sub-sections describing major biosynthetic classes (polyketides, non-ribosomal peptides, terpenoids, meroterpenoids and hybrid biosynthesis). Importantly, we will focus the review on metabolites which have been firmly linked to their corresponding BGCs.

Visualizing the deep cerebellar nuclei using quantitative susceptibility mapping: An application in healthy controls, Parkinson's disease patients and essential tremor patients.

The visualization and identification of the deep cerebellar nuclei (DCN) (dentate [DN], interposed [IN] and fastigial nuclei [FN]) are particularly challenging. We aimed to visualize the DCN using quantitative susceptibility mapping (QSM), predict the contrast differences between QSM and T2* weighted imaging, and compare the DCN volume and susceptibility in movement disorder populations and healthy controls (HCs). Seventy-one Parkinson's disease (PD) patients, 39 essential tremor patients, and 80 HCs were enrolled. The PD patients were subdivided into tremor dominant (TD) and postural instability/gait difficulty (PIGD) groups. A 3D strategically acquired gradient echo MR imaging protocol was used for each subject to obtain the QSM data. Regions of interest were drawn manually on the QSM data to calculate the volume and susceptibility. Correlation analysis between the susceptibility and either age or volume was performed and the intergroup differences of the volume and magnetic susceptibility in all the DCN structures were evaluated. For the most part, all the DCN structures were clearly visualized on the QSM data. The susceptibility increased as a function of volume for both the HC group and disease groups in the DN and IN (p < .001) but not the FN (p = .74). Only the volume of the FN in the TD-PD group was higher than that in the HCs (p = .012), otherwise, the volume and susceptibility among these four groups did not differ significantly. In conclusion, QSM provides clear visualization of the DCN structures. The results for the volume and susceptibility of the DCN can be used as baseline references in future studies of movement disorders.

An automatic interpretable deep learning pipeline for accurate Parkinson's disease diagnosis using quantitative susceptibility mapping and T1-weighted images.

Parkinson's disease (PD) diagnosis based on magnetic resonance imaging (MRI) is still challenging clinically. Quantitative susceptibility maps (QSM) can potentially provide underlying pathophysiological information by detecting the iron distribution in deep gray matter (DGM) nuclei. We hypothesized that deep learning (DL) could be used to automatically segment all DGM nuclei and use relevant features for a better differentiation between PD and healthy controls (HC). In this study, we proposed a DL-based pipeline for automatic PD diagnosis based on QSM and T1-weighted (T1W) images. This consists of (1) a convolutional neural network model integrated with multiple attention mechanisms which simultaneously segments caudate nucleus, globus pallidus, putamen, red nucleus, and substantia nigra from QSM and T1W images, and (2) an SE-ResNeXt50 model with an anatomical attention mechanism, which uses QSM data and the segmented nuclei to distinguish PD from HC. The mean dice values for segmentation of the five DGM nuclei are all >0.83 in the internal testing cohort, suggesting that the model could segment brain nuclei accurately. The proposed PD diagnosis model achieved area under the the receiver operating characteristic curve (AUCs) of 0.901 and 0.845 on independent internal and external testing cohorts, respectively. Gradient-weighted class activation mapping (Grad-CAM) heatmaps were used to identify contributing nuclei for PD diagnosis on patient level. In conclusion, the proposed approach can potentially be used as an automatic, explainable pipeline for PD diagnosis in a clinical setting.

SYNJ2BP Improves the Production of Lentiviral Envelope Protein by Facilitating the Formation of Mitochondrion-Associated Endoplasmic Reticulum Membrane.

Equine infectious anemia virus (EIAV) and HIV are both members of the Lentivirus genus and are similar in major virological characters. EIAV endangers the horse industry. In addition, EIAV can also be used as a model for HIV research. The maturation of the lentiviral Env protein, which is necessary for viral entry, requires Env to be folded in the endoplasmic reticulum (ER). It is currently unclear how this process is regulated. Mitochondrion-associated endoplasmic reticulum membrane (MAM) is a specialized part of the close connection between the ER and mitochondria, and one of the main functions of MAM is to promote oxidative protein production in the ER. SYNJ2BP is one of the key proteins that make up the MAM, and we found that SYNJ2BP is essential for EIAV replication. We therefore constructed a SYNJ2BP knockout HEK293T cell line in which the number of MAMs is significantly reduced. Moreover, overexpression of SYNJ2BP could increase the number of MAMs. Our study demonstrates that SYNJ2BP can improve the infectivity of the EIAV virus with elevated production of the viral Env protein through increased MAM formation. Interestingly, SYNJ2BP was able to improve the production of not only EIAV Env but also HIV. Further investigation showed that MAMs can provide more ATP and calcium ions, which are essential factors for Env production, to the ER and can also reduce ER stress induced by HIV or EIAV Envs to increase the Env production level in cells. These results may help us to understand the key production mechanisms of lentiviral Env. IMPORTANCE Lentiviral Env proteins, which are rich in disulfide bonds, need to be fully folded in the ER; otherwise, misfolded Env proteins will induce ER stress and be degraded by ER-associated protein degradation (ERAD). To date, it is still unclear about Env production mechanism in the ER. MAM is the structure of closely connection between the ER and mitochondria. MAMs play important roles in the calcium steady state and oxidative stress, especially in the production of oxidative protein. For the first time, we found that SYNJ2BP can promote the production of lentiviral Env proteins by providing the ATP and calcium ions required for oxidative protein production in the ER and by reducing ER stress through facilitating formation of MAMs. These studies shed light on how MAMs improve lentiviral Env production, which will lay the foundation for the study of replication mechanisms in other lentiviruses from the perspective of the cellular organelle microenvironment.