The long noncoding RNA glycoLINC assembles a lower glycolytic metabolon to promote glycolysis.

Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.

Reducing the uncertainty in estimating soil microbial-derived carbon storage.

Soil organic carbon (SOC) is the largest carbon pool in terrestrial ecosystems and plays a crucial role in mitigating climate change and enhancing soil productivity. Microbial-derived carbon (MDC) is the main component of the persistent SOC pool. However, current formulas used to estimate the proportional contribution of MDC are plagued by uncertainties due to limited sample sizes and the neglect of bacterial group composition effects. Here, we compiled the comprehensive global dataset and employed machine learning approaches to refine our quantitative understanding of MDC contributions to total carbon storage. Our efforts resulted in a reduction in the relative standard errors in prevailing estimations by an average of 71% and minimized the effect of global variations in bacterial group compositions on estimating MDC. Our estimation indicates that MDC contributes approximately 758 Pg, representing approximately 40% of the global soil carbon stock. Our study updated the formulas of MDC estimation with improving the accuracy and preserving simplicity and practicality. Given the unique biochemistry and functioning of the MDC pool, our study has direct implications for modeling efforts and predicting the land-atmosphere carbon balance under current and future climate scenarios.

Persistent soil carbon enhanced in Mollisols by well-managed grasslands but not annual grain or dairy forage cropping systems.

Intensive crop production on grassland-derived Mollisols has liberated massive amounts of carbon (C) to the atmosphere. Whether minimizing soil disturbance, diversifying crop rotations, or re-establishing perennial grasslands and integrating livestock can slow or reverse this trend remains highly uncertain. We investigated how these management practices affected soil organic carbon (SOC) accrual and distribution between particulate (POM) and mineral-associated (MAOM) organic matter in a 29-y-old field experiment in the North Central United States and assessed how soil microbial traits were related to these changes. Compared to conventional continuous maize monocropping with annual tillage, systems with reduced tillage, diversified crop rotations with cover crops and legumes, or manure addition did not increase total SOC storage or MAOM-C, whereas perennial pastures managed with rotational grazing accumulated more SOC and MAOM-C (18 to 29% higher) than all annual cropping systems after 29 y of management. These results align with a meta-analysis of data from published studies comparing the efficacy of soil health management practices in annual cropping systems on Mollisols worldwide. Incorporating legumes and manure into annual cropping systems enhanced POM-C, microbial biomass, and microbial C-use efficiency but did not significantly increase microbial necromass accumulation, MAOM-C, or total SOC storage. Diverse, rotationally grazed pasture management has the potential to increase persistent soil C on Mollisols, highlighting the key role of well-managed grasslands in climate-smart agriculture.

Unconventional Piezoelectricity of Two-Dimensional Materials Driven by the Hall Effect.

Piezoelectricity has been widely explored for nanoelectromechanical applications, yet its working modes are mainly limited in polar directions. Here we discover the intrinsic electro-mechanical response in crystal materials that is transverse to the conventional polarized direction, which is named unconventional piezoelectricity. A Hall-like mechanism is proposed to interpret unconventional piezoelectricity as charge polarization driven by a built-in electric field for systems with asymmetric Berry curvature distributions. Density functional theory simulations and statistical analyses justify such a mechanism and confirm that unconventional piezoelectricity is a general property for various two-dimensional materials with spin splitting or valley splitting. An empirical formula is derived to connect the conventional and unconventional piezoelectricity. The extended understanding of the piezoelectric tensor in quantum materials opens an opportunity for applications in multidirectional energy conversion, broadband operation, and multifunctional sensing.

Charge Carrier Regulation for Efficient Blue Quantum-Dot Light-Emitting Diodes Via a High-Mobility Coplanar Cyclopentane[b]thiopyran Derivative.

The performance of blue quantum dot light-emitting diodes (QLEDs) is limited by unbalanced charge injection, resulting from insufficient holes caused by low mobility or significant energy barriers. Here, we introduce an angular-shaped heteroarene based on cyclopentane[b]thiopyran (C8-SS) to modify the hole transport layer poly-N-vinylcarbazole (PVK), in blue QLEDs. C8-SS exhibits high hole mobility and conductivity due to the π···π and S···π interactions. Introducing C8-SS to PVK significantly enhanced hole mobility, increasing it by 2 orders of magnitude from 2.44 × 10-6 to 1.73 × 10-4 cm2 V-1 s-1. Benefiting from high mobility and conductivity, PVK:C8-SS-based QLEDs exhibit a low turn-on voltage (Von) of 3.2 V. More importantly, the optimized QLEDs achieve a high peak power efficiency (PE) of 7.13 lm/W, which is 2.65 times that of the control QLEDs. The as-proposed interface engineering provides a novel and effective strategy for achieving high-performance blue QLEDs in low-energy consumption lighting applications.

Unraveling CCL20's role by regulating Th17 cell chemotaxis in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.

Helicobacter pylori CagA protein induces gastric cancer stem cell-like properties through the Akt/FOXO3a axis.

The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter-epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell-like properties in gastric cancer (GC) cells infected with CagA-positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self-renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs-like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA-positive GC cells infected with H. pylori exhibit CSCs-like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA-dependent manner, and our findings suggest that this activation is associated with the CSCs-like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA-dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.

Mitochondrial DNA copy number and cancer risks: A comprehensive Mendelian randomization analysis.

Mitochondrial DNA plays a critical role in the pathophysiology of cancer. However, the associations between mitochondrial DNA copy number (mtDNA-CN) and cancer risk are controversial. Mendelian randomization (MR) analyses were performed using three independent instrumental variables (IVs) to explore potential associations between mtDNA-CN and 20 types of cancer. The three sets of IVs were primarily obtained from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium using different methods. The outcome data of cancers were investigated using summary statistics from the FinnGen cohort. The potential causal associations were evaluated using the MR-Egger regression, weighted median, inverse-variance weighted (IVW), and weighted mode methods. The robustness of IVW estimates was validated using leave-one-out sensitivity analysis. Additionally, a meta-analysis was conducted to pool results from three sets of IVs. The results revealed that genetically predicted mtDNA-CN was not associated with cancer risk (odds ratio = 1.02; 95% confidence interval: 0.95-1.10). Subgroup analyses indicated no causal association between mtDNA-CN and breast, lung, prostate, skin, colorectal, gastric, liver, cervical uteri, esophageal, thyroid, bladder, pancreas, kidney, corpus uteri, ovary, brain, larynx, and anus cancers. It was observed that mtDNA-CN was associated with lip, oral cavity, and testis cancers. However, these results should be interpreted with caution because a small number of patients with lip and oral cavity or testis cancers were included. The comprehensive MR analysis demonstrated that mtDNA-CN is not a suitable biomarker for tumor risk assessment.

Integrated multi-omics analysis and machine learning to refine molecular subtypes, prognosis, and immunotherapy in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) has a malignant characteristic that is highly aggressive and prone to metastasis. There is still a lack of suitable biomarkers to facilitate the refinement of precision-based therapeutic regimens. We used a combination of 10 known clustering algorithms and the omics data from 4 dimensions to identify high-resolution molecular subtypes of LUAD. Subsequently, consensus machine learning-related prognostic signature (CMRS) was developed based on subtypes related genes and an integrated program framework containing 10 machine learning algorithms. The efficiency of CMRS was analyzed from the perspectives of tumor microenvironment, genomic landscape, immunotherapy, drug sensitivity, and single-cell analysis. In terms of results, through multi-omics clustering, we identified 2 comprehensive omics subtypes (CSs) in which CS1 patients had worse survival outcomes, higher aggressiveness, mRNAsi and mutation frequency. Subsequently, we developed CMRS based on 13 key genes up-regulated in CS1. The prognostic predictive efficiency of CMRS was superior to most established LUAD prognostic signatures. CMRS demonstrated a strong correlation with tumor microenvironmental feature variants and genomic instability generation. Regarding clinical performance, patients in the high CMRS group were more likely to benefit from immunotherapy, whereas low CMRS were more likely to benefit from chemotherapy and targeted drug therapy. In addition, we evaluated that drugs such as neratinib, oligomycin A, and others may be candidates for patients in the high CMRS group. Single-cell analysis revealed that CMRS-related genes were mainly expressed in epithelial cells. The novel molecular subtypes identified in this study based on multi-omics data could provide new insights into the stratified treatment of LUAD, while the development of CMRS could serve as a candidate indicator of the degree of benefit of precision therapy and immunotherapy for LUAD.

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Chemistry-Enabled Intercellular Enzymatic Labeling for Monitoring the Immune Effects of Cytotoxic T Lymphocytes In Vivo.

Monitoring the effector function of cytotoxic T lymphocytes (CTLs) in vivo remains a great challenge. Here, we develop a chemistry-enabled enzymatic labeling approach to evaluate the tumor-specific immune response of CTLs by precisely monitoring the interaction between CTLs and tumor cells. Staphylococcus aureus sortase A (SrtA) is linked to the CTL surface through bioconjugate chemistry and then catalyzes the transfer of fluorescent-labeled substrate, 5-Tamra-LPETG, to CTLs. Meanwhile, the tumor cells are specifically decorated with N-terminal glycine residues (G5 peptide) through the inherent glycolmetabolism of cathepsin B-specific cleavable triacetylated N-azidoacetyl-d-mannosamine (CB-Ac3ManNAz) and click chemistry. After the infiltration of engineered CTLs into the tumor tissues, the immune-synapse-mediated specific interaction of CTLs and tumor cells leads to the accurate fluorescent labeling of tumor cells through the SrtA-catalyzed 5-Tamra-LPETG transfer. Therefore, the immune effect of CTLs as well as the performance of immune drugs can be determined, providing a novel strategy for pushing ahead immunotherapy.

Na Substitution Steering RuO6 Unit in Ruthenium Pyrochlores for Enhanced Oxygen Evolution in Acid.

Although Ruthenium-based pyrochlore oxides can function as promising catalysts for acidic water oxidation, their limitations in terms of stability and activity still need to be addressed for further application in practical conditions. In this work, the possibility to enhance both oxygen evolution reaction activity and durability of Gd2Ru2O7- δ through partial replacement with Na+ in Gd3+ sites is first offered, leading to the electronic and geometric regulation of active center RuO6. Na+ triggers the emergence of Ru<4+ and the electron rearrangement of active-centered RuO6. Specifically, Ru ions with a negative d-band center after Na+ doping exhibit weaker adsorption energies of *O and result in the conversion of the rate-limiting step from *O/*OOH to *OH/O*, reducing energy barriers for boosting activities. Therefore, the NaxGd2- xRu2O7- δ requires a low overpotential of 260 mV at 10 mA cm-2 in 0.1 m HClO4 electrolyte. Moreover, the higher formation energy of Ru vacancy and less distorted RuO6 enable the as-prepared NaxGd2- xRu2O7- δ to operate steadily at 10 mA cm-2 for 300 h and multi-current chronopotentiometry with current densities from 20 to 100 mA cm-2 for 60 h in acidic proton exchange membrane electrolyzer, respectively.

A stoichiometric approach to estimate sources of mineral-associated soil organic matter.

Mineral-associated soil organic matter (MAOM) is the largest, slowest cycling pool of carbon (C) in the terrestrial biosphere. MAOM is primarily derived from plant and microbial sources, yet the relative contributions of these two sources to MAOM remain unresolved. Resolving this issue is essential for managing and modeling soil carbon responses to environmental change. Microbial biomarkers, particularly amino sugars, are the primary method used to estimate microbial versus plant contributions to MAOM, despite systematic biases associated with these estimates. There is a clear need for independent lines of evidence to help determine the relative importance of plant versus microbial contributions to MAOM. Here, we synthesized 288 datasets of C/N ratios for MAOM, particulate organic matter (POM), and microbial biomass across the soils of forests, grasslands, and croplands. Microbial biomass is the source of microbial residues that form MAOM, whereas the POM pool is the direct precursor of plant residues that form MAOM. We then used a stoichiometric approach-based on two-pool, isotope-mixing models-to estimate the proportional contribution of plant residue (POM) versus microbial sources to the MAOM pool. Depending on the assumptions underlying our approach, microbial inputs accounted for between 34% and 47% of the MAOM pool, whereas plant residues contributed 53%-66%. Our results therefore challenge the existing hypothesis that microbial contributions are the dominant constituents of MAOM. We conclude that biogeochemical theory and models should account for multiple pathways of MAOM formation, and that multiple independent lines of evidence are required to resolve where and when plant versus microbial contributions are dominant in MAOM formation.

Effect of vitamin D on pregnancy in women with polycystic ovary syndrome: retrospective and prospective studies.

RESEARCH QUESTION: Does vitamin D affect the pregnancy rate of patients with polycystic ovary syndrome (PCOS) receiving ovulation-induction therapy? DESIGN: The retrospective study included 200 patients with PCOS and 200 healthy women. The prospective study included 160 patients with PCOS receiving vitamin D or placebo supplementation. Pregnancy rates were assessed after a maximum of three cycles of ovulation induction. Serum concentrations of 25-hydroxycalciferol [25-(OH)D3], LH, FSH, progesterone, oestradiol, testosterone and fasting insulin; LH/FSH ratio; and body mass index were evaluated. RESULTS: In the retrospective study, patients with PCOS had lower 25-(OH)D3 concentrations than healthy women, pregnant patients with PCOS had higher 25-(OH)D3 concentrations than non-pregnant patients with PCOS (both P = 0.000), and the pregnancy rate was lower in the vitamin-D-deficient group compared with the non-vitamin-D-deficient group (P = 0.022). In the prospective study, compared with placebo supplementation, vitamin D supplementation increased the serum concentration of 25-(OH)D3 (P = 0.000), and reduced the LH/FSH ratio, and concentrations of LH and testosterone significantly (all P ≤ 0.049). After the intervention, it was found that the LH/FSH ratio, and concentrations of LH and testosterone were significantly lower in both groups compared with pre-intervention (P = 0.000). After ovulation induction, the pregnancy rate was higher in patients in the vitamin D supplementation group compared with the placebo supplementation group (P = 0.049). CONCLUSIONS: Vitamin D deficiency is common in patients with PCOS, and vitamin-D-deficient patients with PCOS have lower pregnancy rates after ovulation induction compared with non-vitamin-D-deficient patients with PCOS. Vitamin D supplementation can improve the pregnancy rate and mitigate basic hormone disorders. Therefore, monitoring vitamin D supplementation and checking vitamin D concentrations before and during interventions are essential for patients with PCOS.

Host-Gut Microbiota Metabolic Interactions and Their Role in Precision Diagnosis and Treatment of Gastrointestinal Cancers.

The critical role of the gut microbiome in gastrointestinal cancers is becoming increasingly clear. Imbalances in the gut microbial community, referred to as dysbiosis, are linked to increased risks for various forms of gastrointestinal cancers. Pathogens like Fusobacterium and Helicobacter pylori relate to the onset of esophageal and gastric cancers, respectively, while microbes such as Porphyromonas gingivalis and Clostridium species have been associated with a higher risk of pancreatic cancer. In colorectal cancer, bacteria such as Fusobacterium nucleatum are known to stimulate the growth of tumor cells and trigger cancer-promoting pathways. On the other hand, beneficial microbes like Bifidobacteria offer a protective effect, potentially inhibiting the development of gastrointestinal cancers. The potential for therapeutic interventions that manipulate the gut microbiome is substantial, including strategies to engineer anti-tumor metabolites and employ microbiota-based treatments. Despite the progress in understanding the influence of the microbiome on gastrointestinal cancers, significant challenges remain in identifying and understanding the precise contributions of specific microbial species and their metabolic products. This knowledge is essential for leveraging the role of the gut microbiome in the development of precise diagnostics and targeted therapies for gastrointestinal cancers.

Dendritic cell vaccine for glioblastoma: an updated meta-analysis and trial sequential analysis.

BACKGROUND: Dendritic cell (DC) vaccine is an emerging immunotherapy that could potentially improve glioblastoma survival. The first phase III clinical trial of DC vaccine was recently published. This meta-analysis aims to update and reappraise existing evidence on the efficacy of DC vaccine in patients with glioblastoma. METHODS: We searched PubMed, Embase, and Cochrane Library for clinical trials of DC vaccine for glioblastoma. The quality of the studies was assessed using the RoB 2.0 and ROBINS-I tools. The results of overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Summary effects were evaluated using random effects models. Trial sequential analysis (TSA) was performed. RESULTS: Seven clinical trials involving 3,619 patients were included. DC vaccine plus standard care was associated with significantly improved OS (HR = 0.71; 95% CI, 0.57 - 0.88) and PFS (HR = 0.65; 95% CI, 0.43 - 0.98). In the subgroup of newly diagnosed glioblastoma, DC vaccine was associated with improved PFS (HR = 0.59; 95% CI, 0.39 - 0.90). TSA of OS showed that the cumulative z-score line for the DC vaccine crossed the benefit boundary and reached the required sample size. TSA of PFS and subgroup analysis of newly diagnosed glioblastoma showed that the required sample size was not reached. CONCLUSIONS: This updated meta-analysis, which included the first phase III trial of a DC vaccine for glioblastoma, demonstrated that the DC vaccine was associated with improved OS. Moreover, TSA showed that the required sample size was reached, indicating a true-positive result. Future studies are required for patient subgroups with newly diagnosed and recurrent glioblastoma.

Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors.

Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC50 value of 1.2 µM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development.

Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP.

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4. Of interest, transthyretin upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of transthyretin in frontal temporal lobar degeneration-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioural deficits. Thus, transthyretin conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that transthyretin is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.

Focal ischemic myocardial fibrosis assessed by late gadolinium enhancement cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), ischemic myocardial fibrosis assessed by late gadolinium enhancement (I-LGE) using cardiovascular magnetic resonance (CMR) have been reported. However, the clinical significance of I-LGE has not been completely understood. We aim to evaluate the I-LGE differ phenotypically from HCM without LGE or nonischemic myocardial fibrosis assessed by late gadolinium enhancement (NI-LGE) in the left ventricle (LV). METHODS: The patients with HCM whom was underwent CMR were enrolled, using cine cardiac magnetic resonance to evaluate LV function and LGE to detect the myocardial fibrosis. Three groups were assorted: 1) HCM without LGE; 2) HCM with LGE involved the subendocardial layer was defined as I-LGE; 3) HCM with LGE not involved the subendocardial layer was defined as NI-LGE. RESULTS: We enrolled 122 patients with HCM in the present study. LGE was detected in 58 of 122 (48%) patients with HCM, and 22 (18%) of patients reported I-LGE. HCM with I-LGE had increased higher left ventricular mass index (LVMI) (P < 0.0001) than HCM with NI-LGE or without LGE. In addition, HCM with I-LGE had a larger LV end- systolic volume (P = 0.045), lower LV ejection fraction (LVEF) (P = 0.026), higher LV myocardial mass (P < 0.001) and thicker LV wall (P < 0.001) more than HCM without LGE alone. The I-LGE were significantly associated with LVEF (OR: 0.961; P = 0.016), LV mass (OR: 1.028; P < 0.001), and maximal end-diastolic LVWT (OR: 1.567; P < 0.001). On multivariate analysis, LVEF (OR: 0.948; P = 0.013) and maximal end-diastolic LVWT (OR: 1.548; P = 0.001) were associated with higher risk for I-LGE compared to HCM without LGE. Noticeably, the maximal end-diastolic LVWT (OR: 1.316; P = 0.011) was the only associated with NI-LGE compared to HCM without LGE. CONCLUSIONS: I-LGE is not uncommon in patients with HCM. HCM with I-LGE was associated with significant LV hypertrophy, extensive LGE and poor LV ejection fraction. We should consider focal ischemic myocardial fibrosis when applying LGE to risk stratification for HCM.