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Abstract Background The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer’s disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. Methods We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson’s dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. Results A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [β std] = -0.25, P = 0.01), female (β std = 0.20, P = 0.04), and diabetes mellitus (β std = -0.22, P

Abstract Background Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge. Methods We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival. Results We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell–matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth. Conclusion We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.

Abstract Background Escherichia coli have both the Embden–Meyerhof–Parnas pathway (EMPP) and Entner–Doudoroff pathway (EDP) for glucose breakdown, while the EDP primarily remains inactive for glucose metabolism. However, EDP is a more favorable route than EMPP for the production of certain products. Results EDP was activated by deleting the pfkAB genes in conjunction with subsequent adaptive laboratory evolution (ALE). The evolved strains acquired mutations in transcriptional regulatory genes for glycolytic process (crp, galR, and gntR) and in glycolysis-related genes (gnd, ptsG, and talB). The genotypic, transcriptomic and phenotypic analyses of those mutations deepen our understanding of their beneficial effects on cellulosic biomass bio-conversion. On top of these scientific understandings, we further engineered the strain to produce higher level of lycopene and 3-hydroxypropionic acid. Conclusions These results indicate that the E. coli strain has innate capability to use EDP in lieu of EMPP for glucose metabolism, and this versatility can be harnessed to further engineer E. coli for specific biotechnological applications.

Abstract Background Recent resting-state fMRI studies demonstrated functional dysconnectivity within the central pain matrix in migraineurs. This study aimed to investigate the spatial distribution and amplitude of low-frequency oscillations (LFOs) using fractional amplitude of low-frequency fluctuation (fALFF) analysis in migraine patients without aura, and to examine relationships between regional LFOs and clinical variables. Methods Resting-state fMRI data were obtained and preprocessed in 44 migraine patients without aura and 31 matched controls. fALFF was computed according to the original method, z-transformed for standardization, and compared between migraineurs and controls. Correlation analysis between regional fALFF and clinical variables was performed in migraineurs as well. Results Compared with controls, migraineurs had significant fALFF increases in bilateral ventral posteromedial (VPM) thalamus and brainstem encompassing rostral ventromedial medulla (RVM) and trigeminocervical complex (TCC). Regional fALFF values of bilateral VPM thalamus and brainstem positively correlated with disease duration, but not with migraine attack frequency or Migraine Disability Assessment Scale score. Conclusions We have provided evidence for abnormal LFOs in the brainstem including RVM/TCC and thalamic VPM nucleus in migraine without aura, implicating trigeminothalamic network oscillations in migraine pathophysiology. Our results suggest that enhanced LFO activity may underpin the interictal trigeminothalamic dysrhythmia that could contribute to the impairments of pain transmission and modulation in migraine. Given our finding of increasing fALFF in relation to increasing disease duration, the observed trigeminothalamic dysrhythmia may indicate either an inherent pathology leading to migraine headaches or a consequence of repeated attacks on the brain.